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Tice AL, Steiner JL. Binge alcohol induces NRF2-related antioxidant response in the skeletal muscle of female mice. Biochem Biophys Res Commun 2024; 714:149968. [PMID: 38657445 DOI: 10.1016/j.bbrc.2024.149968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 04/17/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND Chronic alcohol enhances oxidative stress, but the temporal response of antioxidant genes in skeletal muscle following a binge drinking episode remains unknown. METHODS Experiment 1: C57BL/6Hsd female mice received an IP injection of saline (CON; n = 39) or ethanol (ETOH; n = 39) (5 g/kg). Gastrocnemius muscles were collected from baseline (untreated; n = 3), CON (n = 3), and ETOH (n = 3) mice every 4 h for 48 h. Experiment 2: Gastrocnemius muscles were collected from control-fed (CON-FED; n = 17), control-fasted (CON-FAST; n = 18), or alcohol-fed (ETOH-FED; n = 18) mice every 4hrs for 20hrs after saline or ethanol (5 g/kg). RESULTS EtOH enhanced Superoxide dismutase 1 (Sod1) and NADPH Oxidase 4 (Nox4) from 24 to 48hr after the binge, while Sod2 and Nox2 were suppressed. Nuclear factor erythroid-derived 2-like 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) increased 12hrs after intoxication. Cytochrome P450 oxidoreductase (Por), Heme oxygenase 1 (Ho1), Peroxiredoxin 6 (Prdx6), Glutamate-cysteine ligase catalytic subunit (Gclc), Glutamate-cysteine ligase modifier subunit (Gclm), and Glutathione-disulfide reductase (Gsr) were increased by ETOH starting 12-16hrs post-binge. Fasting had similar effects on Nrf2 compared to alcohol, but downstream targets of NRF2, including Por, Ho1, Gclc, and Gclm, were differentially altered with fasting and EtOH. CONCLUSION These data suggest that acute alcohol intoxication induced markers of oxidative stress and antioxidant signaling through the NRF2 pathway and that there were effects of alcohol independent of a possible decrease in food intake caused by binge intoxication.
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Affiliation(s)
- Abigail L Tice
- Department of Health, Nutrition and Food Sciences, Florida State University, 600 W. College Avenue, Tallahassee, FL, 32306, USA
| | - Jennifer L Steiner
- Department of Health, Nutrition and Food Sciences, Florida State University, 600 W. College Avenue, Tallahassee, FL, 32306, USA; Institute of Sports Sciences and Medicine, Florida State University, 600 W. College Avenue, Tallahassee, FL, 32306, USA.
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Wen W, Guo C, Chen Z, Yang D, Zhu D, Jing Q, Zheng L, Sun C, Tang C. Regular exercise attenuates alcoholic myopathy in zebrafish by modulating mitochondrial homeostasis. PLoS One 2023; 18:e0294700. [PMID: 38032938 PMCID: PMC10688687 DOI: 10.1371/journal.pone.0294700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 11/06/2023] [Indexed: 12/02/2023] Open
Abstract
Alcoholic myopathy is caused by chronic consumption of alcohol (ethanol) and is characterized by weakness and atrophy of skeletal muscle. Regular exercise is one of the important ways to prevent or alleviate skeletal muscle myopathy. However, the beneficial effects and the exact mechanisms underlying regular exercise on alcohol myopathy remain unclear. In this study, a model of alcoholic myopathy was established using zebrafish soaked in 0.5% ethanol. Additionally, these zebrafish were intervened to swim for 8 weeks at an exercise intensity of 30% of the absolute critical swimming speed (Ucrit), aiming to explore the beneficial effects and underlying mechanisms of regular exercise on alcoholic myopathy. This study found that regular exercise inhibited protein degradation, improved locomotion ability, and increased muscle fiber cross-sectional area (CSA) in ethanol-treated zebrafish. In addition, regular exercise increases the functional activity of mitochondrial respiratory chain (MRC) complexes and upregulates the expression levels of MRC complexes. Regular exercise can also improve oxidative stress and mitochondrial dynamics in zebrafish skeletal muscle induced by ethanol. Additionally, regular exercise can activate mitochondrial biogenesis and inhibit mitochondrial unfolded protein response (UPRmt). Together, our results suggest regular exercise is an effective intervention strategy to improve mitochondrial homeostasis to attenuate alcoholic myopathy.
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Affiliation(s)
- Wei Wen
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha, China
| | - Cheng Guo
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha, China
| | - Zhanglin Chen
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha, China
| | - Dong Yang
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha, China
| | - Danting Zhu
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha, China
| | - Quwen Jing
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha, China
| | - Lan Zheng
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha, China
| | - Chenchen Sun
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha, China
- School of Physical Education, Hunan First Normal University, Changsha, Hunan, China
| | - Changfa Tang
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha, China
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3
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Ganjayi MS, Brown AM, Baumann CW. Longitudinal assessment of strength and body composition in a mouse model of chronic alcohol-related myopathy. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2023; 47:1653-1664. [PMID: 37431705 DOI: 10.1111/acer.15149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 06/28/2023] [Accepted: 07/03/2023] [Indexed: 07/12/2023]
Abstract
BACKGROUND Excessive, chronic alcohol consumption can result in muscle atrophy and weakness (i.e., alcoholic myopathy) that impairs the quality of life. However, the precise mechanisms responsible for ethanol's detrimental impact on skeletal muscle have not been fully elucidated, in part due because the time course of disease development and progression are not well established. Therefore, we examined muscle strength and body composition longitudinally using an established preclinical mouse model of chronic alcoholic myopathy. METHODS To establish a time course of chronic alcoholic myopathy, we fed High Drinking in the Dark (HDID) female mice (n = 7) 20% ethanol for ~32 weeks (following a 2-week ethanol ramping period). We assessed in vivo isometric contractility of the left ankle dorsiflexor and lean mass via NMR every 4 weeks. Outcomes were compared with age-matched control HDID mice that did not consume ethanol (n = 8). RESULTS At study completion, mice who consumed ethanol were 12% weaker than control mice (p = 0.015). Compared to baseline, consuming ethanol resulted in an acute transient reduction in dorsiflexion torque at Week 4 (p = 0.032) that was followed by a second, more sustained reduction at Week 20 (p < 0.001). Changes in lean mass paralleled those of dorsiflexor torque, with ~40% of the variance in dorsiflexor torque being explained by the variance in lean mass of the ethanol group (p < 0.001). Dorsiflexor torque normalized to lean mass (mN·m/g lean mass) did not differ between the ethanol and control groups from Weeks 4 to 32 (p ≥ 0.498). CONCLUSIONS These results indicate that reductions in muscle mass and strength due to chronic, excessive ethanol intake are dynamic, not necessarily linear, processes. Moreover, the findings confirm that ethanol-induced weakness is primarily driven by muscle atrophy (i.e., loss of muscle quantity). Future studies should consider how chronic alcoholic myopathy develops and progresses rather than identifying changes after it has been diagnosed.
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Affiliation(s)
- Muni Swamy Ganjayi
- Ohio Musculoskeletal and Neurological Institute (OMNI), Ohio University, Athens, Ohio, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
| | - Austin M Brown
- Ohio Musculoskeletal and Neurological Institute (OMNI), Ohio University, Athens, Ohio, USA
- Honors Tutorial College, Ohio University, Athens, Ohio, USA
| | - Cory W Baumann
- Ohio Musculoskeletal and Neurological Institute (OMNI), Ohio University, Athens, Ohio, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
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4
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Alcohol Induces Zebrafish Skeletal Muscle Atrophy through HMGB1/TLR4/NF-κB Signaling. LIFE (BASEL, SWITZERLAND) 2022; 12:life12081211. [PMID: 36013390 PMCID: PMC9410481 DOI: 10.3390/life12081211] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/04/2022] [Accepted: 08/06/2022] [Indexed: 11/17/2022]
Abstract
Excessive alcohol consumption can cause alcoholic myopathy, but the molecular mechanism is still unclear. In this study, zebrafish were exposed to 0.5% alcohol for eight weeks to investigate the effect of alcohol on skeletal muscle and its molecular mechanism. The results showed that the body length, body weight, cross-sectional area of the skeletal muscle fibers, Ucrit, and MO2max of the zebrafish were significantly decreased after alcohol exposure. The expression of markers of skeletal muscle atrophy and autophagy was increased, and the expression of P62 was significantly reduced. The content of ROS, the mRNA expression of sod1 and sod2, and the protein expression of Nox2 were significantly increased. In addition, we found that the inflammatory factors Il1β and Tnfα were significantly enriched in skeletal muscle, and the expression of the HMGB1/TLR4/NF-κB signaling axis was also significantly increased. In summary, in this study, we established a zebrafish model of alcohol-induced skeletal muscle atrophy and further elucidated its pathogenesis.
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Kumar A, Davuluri G, Welch N, Kim A, Gangadhariah M, Allawy A, Priyadarshini A, McMullen MR, Sandlers Y, Willard B, Hoppel CL, Nagy LE, Dasarathy S. Oxidative stress mediates ethanol-induced skeletal muscle mitochondrial dysfunction and dysregulated protein synthesis and autophagy. Free Radic Biol Med 2019; 145:284-299. [PMID: 31574345 PMCID: PMC6910229 DOI: 10.1016/j.freeradbiomed.2019.09.031] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/25/2019] [Accepted: 09/25/2019] [Indexed: 12/21/2022]
Abstract
Protein synthesis and autophagy are regulated by cellular ATP content. We tested the hypothesis that mitochondrial dysfunction, including generation of reactive oxygen species (ROS), contributes to impaired protein synthesis and increased proteolysis resulting in tissue atrophy in a comprehensive array of models. In myotubes treated with ethanol, using unbiased approaches, we identified defects in mitochondrial electron transport chain components, endogenous antioxidants, and enzymes regulating the tricarboxylic acid (TCA) cycle. Using high sensitivity respirometry, we observed impaired cellular respiration, decreased function of complexes I, II, and IV, and a reduction in oxidative phosphorylation in ethanol-treated myotubes and muscle from ethanol-fed mice. These perturbations resulted in lower skeletal muscle ATP content and redox ratio (NAD+/NADH). Ethanol also caused a leak of electrons, primarily from complex III, with generation of mitochondrial ROS and reverse electron transport. Oxidant stress with lipid peroxidation (thiobarbituric acid reactive substances) and protein oxidation (carbonylated proteins) were increased in myotubes and skeletal muscle from mice and humans with alcoholic liver disease. Ethanol also impaired succinate oxidation in the TCA cycle with decreased metabolic intermediates. MitoTEMPO, a mitochondrial specific antioxidant, reversed ethanol-induced mitochondrial perturbations (including reduced oxygen consumption, generation of ROS and oxidative stress), increased TCA cycle intermediates, and reversed impaired protein synthesis and the sarcopenic phenotype. We show that ethanol causes skeletal muscle mitochondrial dysfunction, decreased protein synthesis, and increased autophagy, and that these perturbations are reversed by targeting mitochondrial ROS.
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Affiliation(s)
- Avinash Kumar
- The Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Gangarao Davuluri
- Integrated Physiology and Molecular Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Nicole Welch
- The Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; The Department of Gastroenterology and Hepatology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Adam Kim
- The Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Mahesha Gangadhariah
- The Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Allawy Allawy
- The Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Anupama Priyadarshini
- The Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Megan R McMullen
- The Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Yana Sandlers
- Department of Chemistry, Cleveland State University, Cleveland, OH, USA
| | - Belinda Willard
- The Department of Proteomics Research Core Services, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Charles L Hoppel
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA
| | - Laura E Nagy
- The Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Srinivasan Dasarathy
- The Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; The Department of Gastroenterology and Hepatology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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Abstract
Skeletal muscle atrophy is a common side effect of most human diseases. Muscle loss is not only detrimental for the quality of life but it also dramatically impairs physiological processes of the organism and decreases the efficiency of medical treatments. While hypothesized for years, the existence of an atrophying programme common to all pathologies is still incompletely solved despite the discovery of several actors and key regulators of muscle atrophy. More than a decade ago, the discovery of a set of genes, whose expression at the mRNA levels were similarly altered in different catabolic situations, opened the way of a new concept: the presence of atrogenes, i.e. atrophy-related genes. Importantly, the atrogenes are referred as such on the basis of their mRNA content in atrophying muscles, the regulation at the protein level being sometimes more complicate to elucidate. It should be noticed that the atrogenes are markers of atrophy and that their implication as active inducers of atrophy is still an open question for most of them. While the atrogene family has grown over the years, it has mostly been incremented based on data coming from rodent models. Whether the rodent atrogenes are valid for humans still remain to be established. An "atrogene" was originally defined as a gene systematically up- or down-regulated in several catabolic situations. Even if recent works often restrict this notion to the up-regulation of a limited number of proteolytic enzymes, it is important to keep in mind the big picture view. In this review, we provide an update of the validated and potential rodent atrogenes and the metabolic pathways they belong, and based on recent work, their relevance in human physio-pathological situations. We also propose a more precise definition of the atrogenes that integrates rapid recovery when catabolic stimuli are stopped or replaced by anabolic ones.
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Affiliation(s)
- Daniel Taillandier
- Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, F-63000, Clermont-Ferrand, France.
| | - Cécile Polge
- Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, F-63000, Clermont-Ferrand, France
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7
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Abstract
Both acute intoxication and longer-term cumulative ingestion of alcohol negatively impact the metabolic phenotype of both skeletal and cardiac muscle, independent of overt protein calorie malnutrition, resulting in loss of skeletal muscle strength and cardiac contractility. In large part, these alcohol-induced changes are mediated by a decrease in protein synthesis that in turn is governed by impaired activity of a protein kinase, the mechanistic target of rapamycin (mTOR). Herein, we summarize recent advances in understanding mTOR signal transduction, similarities and differences between the effects of alcohol on this central metabolic controller in skeletal muscle and in the heart, and the effects of acute versus chronic alcohol intake. While alcohol-induced alterations in global proteolysis via activation of the ubiquitin-proteasome pathway are equivocal, emerging data suggest alcohol increases autophagy in muscle. Further studies are necessary to define the relative contributions of these bidirectional changes in protein synthesis and autophagy in the etiology of alcoholic myopathy in skeletal muscle and the heart.
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Affiliation(s)
- Scot R Kimball
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA; ,
| | - Charles H Lang
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA; ,
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8
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Cholecalciferol in ethanol-preferring rats muscle fibers increases the number and area of type II fibers. Acta Histochem 2018; 120:789-796. [PMID: 30224245 DOI: 10.1016/j.acthis.2018.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 09/06/2018] [Accepted: 09/07/2018] [Indexed: 11/21/2022]
Abstract
The chronic use of ethanol causes neuropathy and atrophy of type II fibers and promotes vitamin D decrease. This study evaluated cholecalciferol effects on the deep fibular nerve and extensor digitorum longus (EDL) muscle using an UChB ethanol-preferring rats model. Blood analyses were carried out to measure levels of 25-hydroxycholecalciferol (25(OH)D), calcium (Ca2+), Phosphorus (P), and parathyroid hormone (PTH). It was used EDL muscle to evaluate oxidative stress. The deep fibular nerve and EDL muscle were used for morphologic and morphometric assessment. 25(OH)D plasma levels were higher in the supplemented group and no alterations were observed in other parameters including the oxidative stress evaluation. The G ratio remained constant which indicates nervous conduction normality. Cholecalciferol supplementation promoted an increase in the number and area of type II fibers and a decrease in the area of type I fibers. In the studied model, there was neither alcoholic myopathy nor neuropathy. The EDL muscle glycolytic patterns in the high-drinker UChB rats may be associated with the differential effects of cholecalciferol on metabolism and protein synthesis in skeletal muscle.
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Gritsyna YV, Salmov NN, Bobylev AG, Ulanova AD, Kukushkin NI, Podlubnaya ZA, Vikhlyantsev IM. Increased Autolysis ofμ-Calpain in Skeletal Muscles of Chronic Alcohol-Fed Rats. Alcohol Clin Exp Res 2017; 41:1686-1694. [DOI: 10.1111/acer.13476] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 08/04/2017] [Indexed: 01/31/2023]
Affiliation(s)
- Yulia V. Gritsyna
- Laboratory of Structure and Functions of Muscle Proteins; Institute of Theoretical and Experimental Biophysics; Russian Academy of Sciences; Pushchino Russia
| | - Nikolay N. Salmov
- Laboratory of Structure and Functions of Muscle Proteins; Institute of Theoretical and Experimental Biophysics; Russian Academy of Sciences; Pushchino Russia
| | - Alexander G. Bobylev
- Laboratory of Structure and Functions of Muscle Proteins; Institute of Theoretical and Experimental Biophysics; Russian Academy of Sciences; Pushchino Russia
- Pushchino State Institute of Natural Science; Pushchino Russia
| | - Anna D. Ulanova
- Laboratory of Structure and Functions of Muscle Proteins; Institute of Theoretical and Experimental Biophysics; Russian Academy of Sciences; Pushchino Russia
- Pushchino State Institute of Natural Science; Pushchino Russia
| | - Nikolay I. Kukushkin
- Laboratory of Cell Cultures and Cell Engineering; Institute of Cell Biophysics; Russian Academy of Sciences; Pushchino Russia
| | - Zoya A. Podlubnaya
- Laboratory of Structure and Functions of Muscle Proteins; Institute of Theoretical and Experimental Biophysics; Russian Academy of Sciences; Pushchino Russia
- Pushchino State Institute of Natural Science; Pushchino Russia
| | - Ivan M. Vikhlyantsev
- Laboratory of Structure and Functions of Muscle Proteins; Institute of Theoretical and Experimental Biophysics; Russian Academy of Sciences; Pushchino Russia
- Pushchino State Institute of Natural Science; Pushchino Russia
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Resveratrol-Mediated Expression of KLF15 in the Ischemic Myocardium is Associated with an Improved Cardiac Phenotype. Cardiovasc Drugs Ther 2017; 31:29-38. [PMID: 28064408 DOI: 10.1007/s10557-016-6707-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE Myocardial infarction results in physiological derangements that lead to structural and functional alterations to the myocardium. In addition, oxidative stress potentiates cardiac remodeling and drives disease progression. Unfortunately, treatment with antioxidants in clinical trials have failed to show any therapeutic benefits despite the positive results reported in animal studies, which warrants further investigation into their mechanism(s) of action. Accordingly, the aim of this study was to elucidate a previously unknown mechanism of action for the antioxidant, resveratrol, in the treatment of the ischemic heart. METHODS Male Sprague-Dawley rats underwent four weeks of chronic myocardial ischemia with or without daily resveratrol treatment (10 mg/kg/day). The expression and signaling of Krüppel-like factor 15 (KLF15) were determined by immunoblot and qPCR analyses, respectively. RESULTS Chronic myocardial ischemia reduced the protein expression of KLF15. In parallel, mRNA transcripts of KLF15 gene targets actively involved in cardiac remodeling were robustly increased in untreated hearts. Importantly, daily treatment with resveratrol stimulated KLF15 expression, which was associated with attenuated gene expression and an improved cardiac phenotype. Additionally, we describe a novel role for KLF15 in the regulation of redox homeostasis. CONCLUSION Based on our current findings, it appears that resveratrol treatment induces KLF15 expression, which may, in part, explain its therapeutic efficacy to improve the cardiac phenotype following ischemic injury.
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11
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Baumann CW, Otis JS. 17-(allylamino)-17-demethoxygeldanamycin drives Hsp70 expression but fails to improve morphological or functional recovery in injured skeletal muscle. Clin Exp Pharmacol Physiol 2016; 42:1308-16. [PMID: 26277605 DOI: 10.1111/1440-1681.12477] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 07/23/2015] [Accepted: 08/08/2015] [Indexed: 12/31/2022]
Abstract
The stress inducible 70 kDa heat shock protein (Hsp70) is instrumental to efficient morphological and functional recovery following skeletal muscle injury because of its roles in protein quality control and molecular signalling. Therefore, in attempt to improve recovery, Hsp70 expression was increased with 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) prior to and following an intramuscular injection of barium chloride (BaCl2) into the tibialis anterior (TA) of healthy young mice. To assess recovery, regenerating fibre cross-sectional area (CSA) of the TA and in vivo peak isometric torque produced by the anterior crural muscles (TA, extensor digitorum longus and extensor hallucis muscles) were analyzed for up to 3 weeks after the injury. Because treatment of 17-AAG and Hsp70 are known to influence inflammatory and myogenic signalling, tumor necrosis factor-α (TNF-α) and myogenin content were also assessed. This study reports that 17-AAG was effective at up-regulating Hsp70 expression, increasing content fivefold in the uninjured muscle. However, this significant increase in Hsp70 content did not enhance morphological or functional recovery following the injury, as the return of regenerating fibre CSA and in vivo peak isometric torque did not differ compared to that of the injured muscle from the vehicle treated mice. Treatment with 17-AAG also altered TNF-α and myogenin content, increasing both to a greater extent after the injury. Together, these findings demonstrate that although 17-AAG may alter molecular makers of regeneration, it does not improve recovery following BaCl2-induced skeletal muscle injury in healthy young mice.
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Affiliation(s)
- Cory W Baumann
- Muscle Biology Laboratory, Department of Kinesiology and Health, Georgia State University, Atlanta, GA, USA
| | - Jeffrey S Otis
- Muscle Biology Laboratory, Department of Kinesiology and Health, Georgia State University, Atlanta, GA, USA
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12
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Mehta AJ. Alcoholism and critical illness: A review. World J Crit Care Med 2016; 5:27-35. [PMID: 26855891 PMCID: PMC4733453 DOI: 10.5492/wjccm.v5.i1.27] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/07/2015] [Accepted: 12/04/2015] [Indexed: 02/06/2023] Open
Abstract
Alcohol is the most commonly used and abused drug in the world, and alcohol use disorders pose a tremendous burden to healthcare systems around the world. The lifetime prevalence of alcohol abuse in the United States is estimated to be around 18%, and the economic consequences of these disorders are staggering. Studies on hospitalized patients demonstrate that about one in four patients admitted to critical care units will have alcohol-related issues, and unhealthy alcohol consumption is responsible for numerous clinical problems encountered in intensive care unit (ICU) settings. Patients with alcohol use disorders are not only predisposed to developing withdrawal syndromes and other conditions that often require intensive care, they also experience a considerably higher rate of complications, longer ICU and hospital length of stay, greater resource utilization, and significantly increased mortality compared to similar critically ill patients who do not abuse alcohol. Specific disorders seen in the critical care setting that are impacted by alcohol abuse include delirium, pneumonia, acute respiratory distress syndrome, sepsis, gastrointestinal hemorrhage, trauma, and burn injuries. Despite the substantial burden of alcohol-induced disease in these settings, critical care providers often fail to identify individuals with alcohol use disorders, which can have significant implications for this vulnerable population and delay important clinical interventions.
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13
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Steiner JL, Lang CH. Dysregulation of skeletal muscle protein metabolism by alcohol. Am J Physiol Endocrinol Metab 2015; 308:E699-712. [PMID: 25759394 PMCID: PMC4420901 DOI: 10.1152/ajpendo.00006.2015] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 03/03/2015] [Indexed: 12/12/2022]
Abstract
Alcohol abuse, either by acute intoxication or prolonged excessive consumption, leads to pathological changes in many organs and tissues including skeletal muscle. As muscle protein serves not only a contractile function but also as a metabolic reserve for amino acids, which are used to support the energy needs of other tissues, its content is tightly regulated and dynamic. This review focuses on the etiology by which alcohol perturbs skeletal muscle protein balance and thereby over time produces muscle wasting and weakness. The preponderance of data suggest that alcohol primarily impairs global protein synthesis, under basal conditions as well as in response to several anabolic stimuli including growth factors, nutrients, and muscle contraction. This inhibitory effect of alcohol is mediated, at least in part, by a reduction in mTOR kinase activity via a mechanism that remains poorly defined but likely involves altered protein-protein interactions within mTOR complex 1. Furthermore, alcohol can exacerbate the decrement in mTOR and/or muscle protein synthesis present in other catabolic states. In contrast, alcohol-induced changes in muscle protein degradation, either global or via specific modulation of the ubiquitin-proteasome or autophagy pathways, are relatively inconsistent and may be model dependent. Herein, changes produced by acute intoxication versus chronic ingestion are contrasted in relation to skeletal muscle metabolism, and limitations as well as opportunities for future research are discussed. As the proportion of more economically developed countries ages and chronic illness becomes more prevalent, a better understanding of the etiology of biomedical consequences of alcohol use disorders is warranted.
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Affiliation(s)
- Jennifer L Steiner
- Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania
| | - Charles H Lang
- Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania
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14
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Abstract
Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy. In the past 10 years much has been published about MuRF1 and MAFbx with respect to their mRNA expression patterns under atrophy-inducing conditions, their transcriptional regulation, and their putative substrates. However, much remains to be learned about the physiological role of both genes in the regulation of mass and other cellular functions in striated muscle. Although both MuRF1 and MAFbx are enriched in skeletal, cardiac, and smooth muscle, this review will focus on the current understanding of MuRF1 and MAFbx in skeletal muscle, highlighting the critical questions that remain to be answered.
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Affiliation(s)
- Sue C Bodine
- Departments of Neurobiology, Physiology, and Behavior and Physiology and Membrane Biology, University of California Davis, Davis, California; and Northern California Veterans Affairs Health Systems, Mather, California
| | - Leslie M Baehr
- Membrane Biology, University of California Davis, Davis, California; and
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Otis JS, Niccoli S, Hawdon N, Sarvas JL, Frye MA, Chicco AJ, Lees SJ. Pro-inflammatory mediation of myoblast proliferation. PLoS One 2014; 9:e92363. [PMID: 24647690 PMCID: PMC3960233 DOI: 10.1371/journal.pone.0092363] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 02/20/2014] [Indexed: 01/07/2023] Open
Abstract
Skeletal muscle satellite cell function is largely dictated by the surrounding environment following injury. Immune cell infiltration dominates the extracellular space in the injured area, resulting in increased cytokine concentrations. While increased pro-inflammatory cytokine expression has been previously established in the first 3 days following injury, less is known about the time course of cytokine expression and the specific mechanisms of cytokine induced myoblast function. Therefore, the expression of IL-1β and IL-6 at several time points following injury, and their effects on myoblast proliferation, were examined. In order to do this, skeletal muscle was injured using barium chloride in mice and tissue was collected 1, 5, 10, and 28 days following injury. Mechanisms of cytokine induced proliferation were determined in cell culture using both primary and C2C12 myoblasts. It was found that there is a ∼20-fold increase in IL-1β (p≤0.05) and IL-6 (p = 0.06) expression 5 days following injury. IL-1β increased proliferation of both primary and C2C12 cells ∼25%. IL-1β stimulation also resulted in increased NF-κB activity, likely contributing to the increased proliferation. These data demonstrate for the first time that IL-1β alone can increase the mitogenic activity of primary skeletal muscle satellite cells and offer insight into the mechanisms dictating satellite cell function following injury.
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Affiliation(s)
- Jeffrey S. Otis
- Department of Kinesiology and Health, Georgia State University, Atlanta, Georgia, United States of America
| | - Sarah Niccoli
- Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada
| | - Nicole Hawdon
- Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada
| | - Jessica L. Sarvas
- Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada
- Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada
| | - Melinda A. Frye
- Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America
| | - Adam J. Chicco
- Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado, United States of America
| | - Simon J. Lees
- Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada
- Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada
- Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado, United States of America
- * E-mail:
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Molina PE, Bagby GJ, Nelson S. Biomedical consequences of alcohol use disorders in the HIV-infected host. Curr HIV Res 2014; 12:265-75. [PMID: 25053365 PMCID: PMC4222574 DOI: 10.2174/1570162x12666140721121849] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Revised: 04/08/2014] [Accepted: 04/08/2014] [Indexed: 02/06/2023]
Abstract
Alcohol abuse is the most common and costly form of drug abuse in the United States. It is well known that alcohol abuse contributes to risky behaviors associated with greater incidence of human immunodeficiency virus (HIV) infections. As HIV has become a more chronic disease since the introduction of antiretroviral therapy, it is expected that alcohol use disorders will have an adverse effect on the health of HIV-infected patients. The biomedical consequences of acute and chronic alcohol abuse are multisystemic. Based on what is currently known of the comorbid and pathophysiological conditions resulting from HIV infection in people with alcohol use disorders, chronic alcohol abuse appears to alter the virus infectivity, the immune response of the host, and the progression of disease and tissue injury, with specific impact on disease progression. The combined insult of alcohol abuse and HIV affects organ systems, including the central nervous system, the immune system, the liver, heart, and lungs, and the musculoskeletal system. Here we outline the major pathological consequences of alcohol abuse in the HIV-infected individual, emphasizing its impact on immunomodulation, erosion of lean body mass associated with AIDS wasting, and lipodystrophy. We conclude that interventions focused on reducing or avoiding alcohol abuse are likely to be important in decreasing morbidity and improving outcomes in people living with HIV/AIDS.
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Affiliation(s)
| | | | - Steve Nelson
- LSUHSC Physiology, 1901 Perdido St., New Orleans, LA 70112, USA.
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Gritsyna YV, Salmov NN, Vikhlyantsev IM, Ulanova AD, Sharapov MG, Teplova VV, Podlubnaya ZA. Changes in gene expression and titin (connectin) content in striated muscles of chronically alcoholized rats. Mol Biol 2013. [DOI: 10.1134/s0026893313060058] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Mehta AJ, Yeligar SM, Elon L, Brown LA, Guidot DM. Alcoholism causes alveolar macrophage zinc deficiency and immune dysfunction. Am J Respir Crit Care Med 2013; 188:716-23. [PMID: 23805851 DOI: 10.1164/rccm.201301-0061oc] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
RATIONALE Alcohol use disorders cause oxidative stress in the lower airways and increase susceptibility to pneumonia and lung injury. Currently, no therapeutic options exist to mitigate the pulmonary consequences of alcoholism. OBJECTIVES We recently determined in an animal model that alcohol ingestion impairs pulmonary zinc metabolism and causes alveolar macrophage immune dysfunction. The objective of this research is to determine the effects of alcoholism on zinc bioavailability and alveolar macrophage function in human subjects. METHODS We recruited otherwise healthy alcoholics (n = 17) and matched control subjects (n = 17) who underwent bronchoscopy for isolation of alveolar macrophages, which were analyzed for intracellular zinc, phagocytic function, and surface expression of granulocyte-macrophage colony-stimulating factor receptor; all three of these indices are decreased in experimental models. MEASUREMENTS AND MAIN RESULTS Alcoholic subjects had normal serum zinc, but significantly decreased alveolar macrophage intracellular zinc levels (adjusted means [SE], 718 [41] vs. 948 [25] RFU/cell; P < 0.0001); bacterial phagocytosis (adjusted means [SE], 1,027 [48] vs. 1,509 [76] RFU/cell; P < 0.0001); and expression of granulocyte-macrophage colony-stimulating factor receptor β subunit (adjusted means [SE], 1,471 [42] vs. 2,114 [35] RFU/cell; P < 0.0001]. Treating alveolar macrophages with zinc acetate and glutathione in vitro increased intracellular zinc levels and improved their phagocytic function. CONCLUSIONS These novel clinical findings provide evidence that alcohol abuse is associated with significant zinc deficiency and immune dysfunction within the alveolar space and suggest that dietary supplementation with zinc and glutathione precursors could enhance airway innate immunity and decrease the risk for pneumonia or lung injury in these vulnerable individuals.
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Affiliation(s)
- Ashish J Mehta
- 1 Atlanta Veterans Affairs Medical Center, Decatur, Georgia
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19
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Dekeyser GJ, Clary CR, Otis JS. Chronic alcohol ingestion delays skeletal muscle regeneration following injury. Regen Med Res 2013; 1:2. [PMID: 25984321 PMCID: PMC4376340 DOI: 10.1186/2050-490x-1-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Accepted: 12/21/2012] [Indexed: 12/17/2022] Open
Abstract
Background Chronic alcohol ingestion may cause severe biochemical and pathophysiological derangements to skeletal muscle. Unfortunately, these alcohol-induced events may also prime skeletal muscle for worsened, delayed, or possibly incomplete repair following acute injury. As alcoholics may be at increased risk for skeletal muscle injury, our goals were to identify the effects of chronic alcohol ingestion on components of skeletal muscle regeneration. To accomplish this, age- and gender-matched C57Bl/6 mice were provided normal drinking water or water that contained 20% alcohol (v/v) for 18–20 wk. Subgroups of mice were injected with a 1.2% barium chloride (BaCl2) solution into the tibialis anterior (TA) muscle to initiate degeneration and regeneration processes. Body weights and voluntary wheel running distances were recorded during the course of recovery. Muscles were harvested at 2, 7 or 14 days post-injection and assessed for markers of inflammation and oxidant stress, fiber cross-sectional areas, levels of growth and fibrotic factors, and fibrosis. Results Body weights of injured, alcohol-fed mice were reduced during the first week of recovery. These mice also ran significantly shorter distances over the two weeks following injury compared to uninjured, alcoholics. Injured TA muscles from alcohol-fed mice had increased TNFα and IL6 gene levels compared to controls 2 days after injury. Total protein oxidant stress and alterations to glutathione homeostasis were also evident at 7 and 14 days after injury. Ciliary neurotrophic factor (CNTF) induction was delayed in injured muscles from alcohol-fed mice which may explain, in part, why fiber cross-sectional area failed to normalize 14 days following injury. Gene levels of TGFβ1 were induced early following injury before normalizing in muscle from alcohol-fed mice compared to controls. However, TGFβ1 protein content was consistently elevated in injured muscle regardless of diet. Fibrosis was increased in injured, muscle from alcohol-fed mice at 7 and 14 days of recovery compared to injured controls. Conclusions Chronic alcohol ingestion appears to delay the normal regenerative response following significant skeletal muscle injury. This is evidenced by reduced cross-sectional areas of regenerated fibers, increased fibrosis, and altered temporal expression of well-described growth and fibrotic factors.
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Affiliation(s)
- Graham J Dekeyser
- Department of Kinesiology and Health, Georgia State University, Atlanta, GA 30322 USA
| | | | - Jeffrey S Otis
- Department of Kinesiology and Health, Georgia State University, Atlanta, GA 30322 USA
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Korzick DH, Sharda DR, Pruznak AM, Lang CH. Aging accentuates alcohol-induced decrease in protein synthesis in gastrocnemius. Am J Physiol Regul Integr Comp Physiol 2013; 304:R887-98. [PMID: 23535459 DOI: 10.1152/ajpregu.00083.2013] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The present study sought to determine whether the protein catabolic response in skeletal muscle produced by chronic alcohol feeding was exaggerated in aged rats. Adult (3 mo) and aged (18 mo) female F344 rats were fed a nutritionally complete liquid diet containing alcohol (36% of total calories) or an isocaloric isonitrogenous control diet for 20 wk. Muscle (gastrocnemius) protein synthesis, as well as mTOR and proteasome activity did not differ between control-fed adult and aged rats, despite the increased TNF-α and IL-6 mRNA and decreased IGF-I mRNA in muscle of aged rats. Compared with alcohol-fed adult rats, aged rats demonstrated an exaggerated alcohol-induced reduction in lean body mass and protein synthesis (both sarcoplasmic and myofibrillar) in gastrocnemius. Alcohol-fed aged rats had enhanced dephosphorylation of 4E-BP1, as well as enhanced binding of raptor with both mTOR and Deptor, and a decreased binding of raptor with 4E-BP1. Alcohol feeding of both adult and aged rats reduced RagA binding to raptor. The LKB1-AMPK-REDD1 pathway was upregulated in gastrocnemius from alcohol-fed aged rats. These exaggerated alcohol-induced effects in aged rats were associated with a greater decrease in muscle but not circulating IGF-I, but no further increase in inflammatory mediators. In contrast, alcohol did not exaggerate the age-induced increase in atrogin-1 and MuRF1 mRNA or the increased proteasome activity. Our results demonstrate that, compared with adult rats, the gastrocnemius from aged rats is more sensitive to the catabolic effects of alcohol on protein synthesis, but not protein degradation, and this exaggerated response may be AMPK-dependent.
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Affiliation(s)
- Donna H Korzick
- Department of Kinesiology, The Pennsylvania State University, University Park, PA, USA
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21
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Pruznak AM, Nystrom J, Lang CH. Direct central nervous system effect of alcohol alters synthesis and degradation of skeletal muscle protein. Alcohol Alcohol 2012; 48:138-45. [PMID: 23079499 DOI: 10.1093/alcalc/ags113] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
AIMS Alcohol can directly impair protein synthesis in cultured myocytes as well as in in situ perfused skeletal muscle. However, alcohol in the general circulation diffuses rapidly into the central nervous system (CNS). Therefore, this study determined whether localized elevation of alcohol within the CNS is capable of decreasing muscle protein synthesis. METHODS Conscious unstrained male rats received a continuous intracerebroventricular (ICV) infusion of ethanol and skeletal muscle protein synthesis and degradation were assessed. RESULTS ICV alcohol decreased protein synthesis in the gastrocnemius after 6 and 24 h, compared with the time-matched controls. The reduction was equivalent for both sarcoplasmic and myofibrillar proteins and was reversible. The inhibitory effect of alcohol was not prevented by the catalase inhibitor 3-amino-1,2,4-triazole and was mimicked by ICV-administered t-butanol. The alcohol-induced decrease in muscle protein synthesis was associated with a concomitant reduction in phosphorylation of 4E-binding protein and ribosomal S6 kinase-1, suggesting impaired mammalian target of rapamycin kinase activity. ICV alcohol also impaired the ability of leucine to stimulate protein synthesis. Conversely, ICV alcohol increased muscle proteasome activity and muscle RING-finger protein-1 mRNA content. Altered muscle protein metabolism was not associated with changes in muscle mRNA content for tumor necrosis factor α, interleukin-6 or insulin-like growth factor (IGF)-I or circulating insulin or IGF-I. CONCLUSION Selective elevation of alcohol within the CNS is capable of decreasing protein synthesis and increasing protein degradation in muscle in the absence of alcohol in the general circulation, thus revealing a previously unrecognized central neural mechanism, which may account for part of the inhibitory effect of ingested alcohol on muscle protein homeostasis.
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Affiliation(s)
- Anne M Pruznak
- Department of Cellular & Molecular Physiology, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
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Al Moutaery M, Al Rayes H, Al Swailam R, Elfaki I, Khan HA, Arshaduddin M, Tariq M. Protective effect of a cysteine prodrug and antioxidant, L-2-oxothiazolidine-4-carboxylate, against ethanol-induced gastric lesions in rats. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY : OFFICIAL JOURNAL OF THE GESELLSCHAFT FUR TOXIKOLOGISCHE PATHOLOGIE 2012; 64:233-7. [PMID: 20829008 DOI: 10.1016/j.etp.2010.08.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2010] [Revised: 08/12/2010] [Accepted: 08/15/2010] [Indexed: 02/05/2023]
Abstract
Earlier studies have suggested an important role of glutathione (GSH) in cytoprotection against free radicals induced oxidative damage. This study reports gastroprotective effects of a cysteine precursor, L-2-oxothiazolidine-4-carboxylate (OTC), in experimental models of gastric secretion and ulceration. Acid secretion studies (volume and acidity) were undertaken in pylorus-ligated rats whereas the gastric lesions were induced by ethanol. Different groups of animals were treated with OTC (0, 100, 200 and 400 mg/kg). The levels of gastric wall mucus, nonprotein sulfhydryls (NP-SH) and myeloperoxidase (MPO) were measured in the glandular stomach of rats following ethanol-induced gastric lesions. Both medium and high doses of OTC significantly reduced the volume and acidity of gastric secretion in pylorus-ligated rats. Pretreatment with OTC significantly and dose-dependently attenuated the formation of ethanol-induced gastric lesion. OTC significantly protected the gastric mucosa against ethanol-induced depletion of gastric wall mucus, NP-SH and MPO. The gastroprotective effects of OTC may be attributed to its ability to inhibit neutrophils activity and replenish GSH demand.
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Affiliation(s)
- Meshal Al Moutaery
- Prince Sultan Cardiac Center, Armed Forces Hospital, Riyadh, Saudi Arabia
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Sobral-Oliveira MB, Faintuch J, Guarita DR, Oliveira CP, Carrilho FJ. Nutritional profile of asymptomatic alcoholic patients. ARQUIVOS DE GASTROENTEROLOGIA 2012; 48:112-8. [PMID: 21709952 DOI: 10.1590/s0004-28032011000200006] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2010] [Accepted: 11/10/2010] [Indexed: 02/07/2023]
Abstract
CONTEXT Alcoholism may interfere with nutritional status, but reports are often troubled by uncertainties about ingested diet and organ function, as well as by ongoing abuse and associated conditions. OBJECTIVE To identify nutritional and body compartment changes in stable alcoholics without confounding clinical and dietetic variables, a prospective observational pilot study was designed. Three well-matched populations were considered: subjects with chronic alcoholic pancreatitis, alcoholics without visceral disease, and healthy never-drinking adults (controls). METHODS Subjects (n = 60) were asymptomatic males with adequate diet, no superimposed disease or complication, and alcohol-free for at least 6 months. After exclusions, 48 patients were compared. Variables encompassed dietary recall, bioimpedance analysis, biochemical profile and inflammatory markers. Main outcome measures were body fat, lean body mass, serum lipids, C-reactive protein, and selected minerals and vitamins. RESULTS Both alcoholic populations suffered from reduced lean body mass (P = 0.001), with well-maintained body fat.Magnesium was depleted, and values of vitamin D and B12 correlated with alcohol abuse. LDL and total cholesterol was increased in alcoholics without pancreatitis (P = 0.04), but not in those with visceral damage. C-reactive protein and serum amyloid A correlated with duration of excessive drinking (P = 0.01). CONCLUSIONS Undernutrition (diminished lean body mass, risk of magnesium and vitamin deficiencies) contrasted with dyslipidemia and increased cardiovascular risk. This second danger was masked during chronic pancreatitis but not in alcoholics without visceral disease. Further studies should focus special requirements of this population.
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Clary CR, Guidot DM, Bratina MA, Otis JS. Chronic alcohol ingestion exacerbates skeletal muscle myopathy in HIV-1 transgenic rats. AIDS Res Ther 2011; 8:30. [PMID: 21846370 PMCID: PMC3170178 DOI: 10.1186/1742-6405-8-30] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Accepted: 08/16/2011] [Indexed: 12/12/2022] Open
Abstract
Background Separately, chronic alcohol ingestion and HIV-1 infection are associated with severe skeletal muscle derangements, including atrophy and wasting, weakness, and fatigue. One prospective cohort study reported that 41% of HIV-infected patients met the criteria for alcoholism, however; few reports exist on the co-morbid effects of these two disease processes on skeletal muscle homeostasis. Thus, we analyzed the atrophic effects of chronic alcohol ingestion in HIV-1 transgenic rats and identified alterations to several catabolic and anabolic factors. Findings Relative plantaris mass, total protein content, and fiber cross-sectional area were reduced in each experimental group compared to healthy, control-fed rats. Alcohol abuse further reduced plantaris fiber area in HIV-1 transgenic rats. Consistent with previous reports, gene levels of myostatin and its receptor activin IIB were not increased in HIV-1 transgenic rat muscle. However, myostatin and activin IIB were induced in healthy and HIV-1 transgenic rats fed alcohol for 12 weeks. Catabolic signaling factors such as TGFβ1, TNFα, and phospho-p38/total-p38 were increased in all groups compared to controls. There was no effect on IL-6, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), or ciliary neurotrophic factor (CNTF) in control-fed, transgenic rats. However, the co-morbidity of chronic alcohol abuse and HIV-1-related protein expression decreased expression of the two anabolic factors, CT-1 and CNTF. Conclusions Consistent with previous reports, alcohol abuse accentuated skeletal muscle atrophy in an animal model of HIV/AIDS. While some catabolic pathways known to drive alcoholic or HIV-1-associated myopathies were also elevated in this co-morbid model (e.g., TGFβ1), consistent expression patterns were not apparent. Thus, specific alterations to signaling mechanisms such as the induction of the myostatin/activin IIB system or reductions in growth factor signaling via CT-1- and CNTF-dependent mechanisms may play larger roles in the regulation of muscle mass in alcoholic, HIV-1 models.
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The role and regulation of MAFbx/atrogin-1 and MuRF1 in skeletal muscle atrophy. Pflugers Arch 2011; 461:325-35. [DOI: 10.1007/s00424-010-0919-9] [Citation(s) in RCA: 203] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2010] [Accepted: 12/21/2010] [Indexed: 10/18/2022]
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Jung MK, Callaci JJ, Lauing KL, Otis JS, Radek KA, Jones MK, Kovacs EJ. Alcohol exposure and mechanisms of tissue injury and repair. Alcohol Clin Exp Res 2010; 35:392-9. [PMID: 21118273 DOI: 10.1111/j.1530-0277.2010.01356.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Tissue injury owing to acute and chronic alcohol consumption has extensive medical consequences, with the level and duration of alcohol exposure affecting both the magnitude of injury and the time frame to recovery. While the understanding of many of the molecular processes disrupted by alcohol has advanced, mechanisms of alcohol-induced tissue injury remain a subject of intensive research. Alcohol has multiple targets, as it affects diverse cellular and molecular processes. Some mechanisms of tissue damage as a result of alcohol may be common to many tissue types, while others are likely to be tissue specific. Here, we present a discussion of the alcohol-induced molecular and cellular disruptions associated with injury or recovery from injury in bone, muscle, skin, and gastric mucosa. In every case, the goal of characterizing the sites of alcohol action is to devise potential measures for protection, prevention, or therapeutic intervention.
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Affiliation(s)
- M Katherine Jung
- Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9304, USA.
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Otis JS, Guidot DM. Procysteine increases alcohol-depleted glutathione stores in rat plantaris following a period of abstinence. Alcohol Alcohol 2010; 45:495-500. [PMID: 20935073 PMCID: PMC2981520 DOI: 10.1093/alcalc/agq066] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Aims: To assess the effectiveness of procysteine (PRO) supplementation provided during a period of abstinence (ABS) on alcohol-induced skeletal muscle atrophy and oxidant stress. Methods: Age- and gender-matched Sprague–Dawley rats were fed the Lieber–DeCarli liquid diet containing either alcohol or an isocaloric substitution (control diet) for 12 week. Next, subgroups of alcohol-fed rats were fed the control diet for 2 week (ABS) supplemented with either PRO (0.35%, w/v) or vehicle. Plantaris morphology was assessed by hematoxylin and eosin staining. Total, reduced and oxidized glutathione (GSH) levels and total antioxidant potential were determined by commercially available assay kits. Antibody arrays were used to determine cytokine levels. Real-time polymerase chain reaction was used to determine gene expressions of two E3 ubiquitin ligases, atrogin-1 and muscle ring finger protein-1 (MuRF-1). Results: Plantaris muscles from alcohol-fed rats displayed extensive atrophy, as well as decreased GSH levels, a trend for decreased total antioxidant potential and elevated atrogin-1 and MuRF-1 mRNA levels. GSH levels and total antioxidant potential continued to decrease during 2 weeks of ABS from alcohol, which were normalized in abstinent rats provided PRO. Gene levels of both E3 ligases returned to baseline during ABS. In parallel, plantaris cross-sectional area increased in both groups during ABS. Conclusions: PRO supplementation during ABS significantly attenuated alcohol-induced redox stress compared with untreated abstinent rats. Thus, our data may suggest that GSH restoration therapy may provide therapeutic benefits to the overall antioxidant state of skeletal muscle when prescribed in conjunction with an established detoxification program for recovering alcoholics.
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Affiliation(s)
- Jeffrey S Otis
- Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University School of Medicine, Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, GA 30322, USA.
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Jung SE, Kim YK, Youn DY, Lim MH, Ko JH, Ahn YS, Lee JH. Down-modulation of Bis sensitizes cell death in C6 glioma cells induced by oxygen–glucose deprivation. Brain Res 2010; 1349:1-10. [DOI: 10.1016/j.brainres.2010.06.043] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2010] [Revised: 06/15/2010] [Accepted: 06/18/2010] [Indexed: 12/28/2022]
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