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Sausa M, Fucarino A, Paladino L, Zummo FP, Fabbrizio A, Di Felice V, Rappa F, Barone R, Marino Gammazza A, Macaluso F. Probiotics as Potential Therapeutic Agents: Safeguarding Skeletal Muscle against Alcohol-Induced Damage through the Gut-Liver-Muscle Axis. Biomedicines 2024; 12:382. [PMID: 38397983 PMCID: PMC10886686 DOI: 10.3390/biomedicines12020382] [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: 12/18/2023] [Revised: 02/03/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Probiotics have shown the potential to counteract the loss of muscle mass, reduce physical fatigue, and mitigate inflammatory response following intense exercise, although the mechanisms by which they work are not very clear. The objective of this review is to describe the main harmful effects of alcohol on skeletal muscle and to provide important strategies based on the use of probiotics. The excessive consumption of alcohol is a worldwide problem and has been shown to be crucial in the progression of alcoholic liver disease (ALD), for which, to date, the only therapy available is lifestyle modification, including cessation of drinking. In ALD, alcohol contributes significantly to the loss of skeletal muscle, and also to changes in the intestinal microbiota, which are the basis for a series of problems related to the onset of sarcopenia. Some of the main effects of alcohol on the skeletal muscle are described in this review, with particular emphasis on the "gut-liver-muscle axis", which seems to be the primary cause of a series of muscle dysfunctions related to the onset of ALD. The modulation of the intestinal microbiota through probiotics utilization has appeared to be crucial in mitigating the muscle damage induced by the high amounts of alcohol consumed.
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Affiliation(s)
- Martina Sausa
- Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy; (M.S.); (A.F.); (A.F.)
| | - Alberto Fucarino
- Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy; (M.S.); (A.F.); (A.F.)
| | - Letizia Paladino
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
| | - Francesco Paolo Zummo
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
| | - Antonio Fabbrizio
- Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy; (M.S.); (A.F.); (A.F.)
| | - Valentina Di Felice
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
| | - Francesca Rappa
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
| | - Rosario Barone
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
| | - Antonella Marino Gammazza
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
| | - Filippo Macaluso
- Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy; (M.S.); (A.F.); (A.F.)
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
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Abstract
PURPOSE Alcohol-related myopathy is one of the earliest alcohol-associated pathological tissue changes that is progressively exacerbated by cumulative long-term alcohol misuse. Acute and chronic alcohol use leads to changes in skeletal muscle mass and function. As discussed in this evidence-based review, alcohol-mediated mechanisms are multifactorial with effects on anabolic and catabolic signaling, mitochondrial bioenergetics, extracellular matrix remodeling, and epigenomic alterations. However, systematic studies are limited, especially regarding the acute effects of alcohol on skeletal muscle. SEARCH METHODS This review focuses on peer-reviewed manuscripts published between January 2012 and November 2022 using the search terms "alcohol" or "ethanol" and "skeletal muscle" in MEDLINE, PubMed, and Web of Science using EndNote reference management software. SEARCH RESULTS Eligible manuscripts included full-length research papers that discussed acute and chronic effects of alcohol on skeletal muscle mass and function in both clinical and preclinical studies. The review also includes alcohol-mediated skeletal muscle effects in the context of comorbidities. The three databases together yielded 708 manuscripts. Of these, the authors excluded from this review 548 papers that did not have "alcohol" or "muscle" in the title and 64 papers that were duplicates or did not discuss skeletal muscle. Thus, of all the manuscripts considered for this review, 96 are included and 612 are excluded. Additionally, relevant papers published earlier than 2012 are included to provide context to the review. DISCUSSION AND CONCLUSIONS Both acute and chronic alcohol use decrease protein synthesis and increase protein degradation. Alcohol also impairs mitochondrial function and extracellular matrix remodeling. However, there is a gap in the literature on the known alcohol-mediated mechanisms, including senescence, role of immune activation, and interorgan communication, on the development of alcohol-related myopathy. With increased life expectancy, changing alcohol use patterns, and increasing frequency of alcohol use among females, current observational studies are needed on the prevalence of alcohol-related myopathy. Additionally, the compounding effects of acute and chronic alcohol use on skeletal muscle with aging or exercise, in response to injury or disuse, and in the context of comorbidities including diabetes and human immunodeficiency virus (HIV), call for further investigation. Though evidence suggests that abstinence or reducing alcohol use can improve muscle mass and function, they are not restored to normal levels. Hence, understanding the pathophysiological mechanisms can help in the design of therapeutic strategies to improve skeletal muscle health.
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Affiliation(s)
- Liz Simon
- Department of Physiology and Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Brianna L Bourgeois
- Department of Physiology and Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Patricia E Molina
- Department of Physiology and Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana
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Romero-Herrera I, Nogales F, Diaz-Castro J, Moreno-Fernandez J, Gallego-Lopez MDC, Ochoa JJ, Carreras O, Ojeda ML. Binge drinking leads to an oxidative and metabolic imbalance in skeletal muscle during adolescence in rats: endocrine repercussion. J Physiol Biochem 2023; 79:799-810. [PMID: 37676577 PMCID: PMC10635949 DOI: 10.1007/s13105-023-00983-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 08/26/2023] [Indexed: 09/08/2023]
Abstract
Binge drinking (BD) is an especially pro-oxidant model of alcohol consumption, mainly used by adolescents. It has recently been related to the hepatic IR-process. Skeletal muscle is known to be involved in insulin action and modulation through myokine secretion. However, there is no information on muscle metabolism and myokine secretion after BD exposure in adolescents. Two experimental groups of adolescent rats have been used: control and BD-exposed one. Oxidative balance, energy status and lipid, and protein metabolism have been analyzed in muscle, together with myokine serum levels (IL-6, myostatin, LIF, IL-5, fractalkine, FGF21, irisin, BDNF, FSTL1, apelin, FABP3, osteocrin, osteonectin (SPARC), and oncostatin). In muscle, BD affects the antioxidant enzyme balance leading to lipid and protein oxidation. Besides, it also increases the activation of AMPK and thus contributes to decrease SREBP1 and pmTOR and to increase FOXO3a expressions, promoting lipid and protein degradation. These alterations deeply affect the myokine secretion pattern. This is the first study to examine a general myokine response after exposure to BD. BD not only caused a detrimental imbalance in myokines related to muscle turnover, decreased those contributing to increase IR-process, decreased FST-1 and apelin and their cardioprotective function but also reduced the neuroprotective BDNF. Consequently, BD leads to an important metabolic and energetic disequilibrium in skeletal muscle, which contributes to exacerbate a general IR-process.
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Affiliation(s)
- Inés Romero-Herrera
- Department of Physiology, Faculty of Pharmacy, Seville University, n° 2, 41012, Seville, Spain
| | - Fátima Nogales
- Department of Physiology, Faculty of Pharmacy, Seville University, n° 2, 41012, Seville, Spain.
| | - Javier Diaz-Castro
- Institute of Nutrition and Food Technology "José Mataix Verdú", University of Granada, Avenida del Conocimiento s/n, 18071, Armilla, Granada, Spain
- Department of Physiology, University of Granada, Granada, Spain
| | - Jorge Moreno-Fernandez
- Institute of Nutrition and Food Technology "José Mataix Verdú", University of Granada, Avenida del Conocimiento s/n, 18071, Armilla, Granada, Spain
- Department of Physiology, University of Granada, Granada, Spain
| | | | - Julio J Ochoa
- Institute of Nutrition and Food Technology "José Mataix Verdú", University of Granada, Avenida del Conocimiento s/n, 18071, Armilla, Granada, Spain
- Department of Physiology, University of Granada, Granada, Spain
| | - Olimpia Carreras
- Department of Physiology, Faculty of Pharmacy, Seville University, n° 2, 41012, Seville, Spain
| | - María Luisa Ojeda
- Department of Physiology, Faculty of Pharmacy, Seville University, n° 2, 41012, Seville, Spain
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Prado GHJD, Sardeli AV, Lord JM, Cavaglieri CR. The effects of ageing, BMI and physical activity on blood IL-15 levels: A systematic review and meta-analyses. Exp Gerontol 2022; 168:111933. [PMID: 36007720 DOI: 10.1016/j.exger.2022.111933] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022]
Abstract
AIM The purpose of the study was to test the effect of ageing, BMI, physical activity and chronic exercise on IL-15 blood concentration by meta-analyses of the literature. METHODS The search was performed on PubMed/MEDLINE, Web of Science, ProQuest, Embase and Cochrane databases. First meta-analysis compared blood IL-15 of healthy adults across three age groups (<35 years, 35-65 years, and >65 years), considering BMI as confounding factor; the second compared IL-15 levels between physically active and non-physically active individuals (cross-sectional studies); and the third tested the effect of chronic exercise interventions on blood IL-15 levels on participants of any age, sex, and health condition. RESULTS From 2582 studies retrieved, 67 were selected for the three meta-analyses (age effect: 59; physical activity cross-sectional effect: 5; chronic exercise effect: 14). Older adults had lower blood IL-15 than young and middle-aged adults (5.30 pg/ml [4.76; 5.83]; 7.11 pg/ml [6.33; 7.88]; 7.10 pg/ml [5.55; 8.65], respectively). However, the subgroup of overweight older adults had higher IL-15 than young and middle aged overweight adults; Habitual physical activity did not affect blood IL-15 (standardized mean difference [SMD] 0.61 [-0.65; 1.88], p = 0.34); Chronic exercise reduced blood IL-15 in short-term interventions (<16 weeks) (SMD -0.14 [-0.27; -0.01], p = 0.04), but not studies of >16 weeks of intervention (SMD 0.44 [-0.26; 1.15], p = 0.22). CONCLUSION The present meta-analyses highlight the complex interaction of age, BMI and physical activity on blood IL-15 and emphasize the need to take these factors into account when considering the role of this myokine in health throughout life.
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Affiliation(s)
| | - Amanda Veiga Sardeli
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas, SP, Brazil; Gerontology Program, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil; MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK.
| | - Janet Mary Lord
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
| | - Cláudia Regina Cavaglieri
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas, SP, Brazil; Gerontology Program, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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Klyne DM, Barbe MF, James G, Hodges PW. Does the Interaction between Local and Systemic Inflammation Provide a Link from Psychology and Lifestyle to Tissue Health in Musculoskeletal Conditions? Int J Mol Sci 2021; 22:ijms22147299. [PMID: 34298917 PMCID: PMC8304860 DOI: 10.3390/ijms22147299] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/02/2021] [Accepted: 07/04/2021] [Indexed: 01/02/2023] Open
Abstract
Musculoskeletal conditions are known to involve biological, psychological, social and, often, lifestyle elements. However, these domains are generally considered in isolation from each other. This siloed approach is unlikely to be adequate to understand the complexity of these conditions and likely explains a major component of the disappointing effects of treatment. This paper presents a hypothesis that aims to provide a foundation to understand the interaction and integration between these domains. We propose a hypothesis that provides a plausible link between psychology and lifestyle factors with tissue level effects (such as connective tissue dysregulation/accumulation) in musculoskeletal conditions that is founded on understanding the molecular basis for interaction between systemic and local inflammation. The hypothesis provides plausible and testable links between mind and body, for which empirical evidence can be found for many aspects. We present this hypothesis from the perspective of connective tissue biology and pathology (fibrosis), the role of inflammation locally (tissue level), and how this inflammation is shaped by systemic inflammation through bidirectional pathways, and various psychological and lifestyle factors via their influence on systemic inflammation. This hypothesis provides a foundation for new consideration of the development and refinement of personalized multidimensional treatments for individuals with musculoskeletal conditions.
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Affiliation(s)
- David M. Klyne
- NHMRC Centre of Clinical Research Excellence in Spinal Pain, Injury and Health, School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane 4072, Australia; (G.J.); (P.W.H.)
- Correspondence: ; Tel.: +61-7-3365-4569
| | - Mary F. Barbe
- Department of Anatomy and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA;
| | - Greg James
- NHMRC Centre of Clinical Research Excellence in Spinal Pain, Injury and Health, School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane 4072, Australia; (G.J.); (P.W.H.)
| | - Paul W. Hodges
- NHMRC Centre of Clinical Research Excellence in Spinal Pain, Injury and Health, School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane 4072, Australia; (G.J.); (P.W.H.)
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Zahr NM, Pohl KM, Kwong AJ, Sullivan EV, Pfefferbaum A. Preliminary Evidence for a Relationship between Elevated Plasma TNFα and Smaller Subcortical White Matter Volume in HCV Infection Irrespective of HIV or AUD Comorbidity. Int J Mol Sci 2021; 22:ijms22094953. [PMID: 34067023 PMCID: PMC8124321 DOI: 10.3390/ijms22094953] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/08/2023] Open
Abstract
Classical inflammation in response to bacterial, parasitic, or viral infections such as HIV includes local recruitment of neutrophils and macrophages and the production of proinflammatory cytokines and chemokines. Proposed biomarkers of organ integrity in Alcohol Use Disorders (AUD) include elevations in peripheral plasma levels of proinflammatory proteins. In testing this proposal, previous work included a group of human immunodeficiency virus (HIV)-infected individuals as positive controls and identified elevations in the soluble proteins TNFα and IP10; these cytokines were only elevated in AUD individuals seropositive for hepatitis C infection (HCV). The current observational, cross-sectional study evaluated whether higher levels of these proinflammatory cytokines would be associated with compromised brain integrity. Soluble protein levels were quantified in 86 healthy controls, 132 individuals with AUD, 54 individuals seropositive for HIV, and 49 individuals with AUD and HIV. Among the patient groups, HCV was present in 24 of the individuals with AUD, 13 individuals with HIV, and 20 of the individuals in the comorbid AUD and HIV group. Soluble protein levels were correlated to regional brain volumes as quantified with structural magnetic resonance imaging (MRI). In addition to higher levels of TNFα and IP10 in the 2 HIV groups and the HCV-seropositive AUD group, this study identified lower levels of IL1β in the 3 patient groups relative to the control group. Only TNFα, however, showed a relationship with brain integrity: in HCV or HIV infection, higher peripheral levels of TNFα correlated with smaller subcortical white matter volume. These preliminary results highlight the privileged status of TNFα on brain integrity in the context of infection.
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Affiliation(s)
- Natalie M. Zahr
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; (K.M.P.); (A.P.)
- Neuroscience Program, SRI International, Menlo Park, CA 94025, USA;
- Correspondence: ; Tel.: +1-650-859-5243
| | - Kilian M. Pohl
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; (K.M.P.); (A.P.)
- Neuroscience Program, SRI International, Menlo Park, CA 94025, USA;
| | - Allison J. Kwong
- Gastroenterology and Hepatology Medicine, Stanford University School of Medicine, Stanford, CA 94350, USA;
| | | | - Adolf Pfefferbaum
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; (K.M.P.); (A.P.)
- Neuroscience Program, SRI International, Menlo Park, CA 94025, USA;
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García-Baos A, Alegre-Zurano L, Cantacorps L, Martín-Sánchez A, Valverde O. Role of cannabinoids in alcohol-induced neuroinflammation. Prog Neuropsychopharmacol Biol Psychiatry 2021; 104:110054. [PMID: 32758518 DOI: 10.1016/j.pnpbp.2020.110054] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/13/2020] [Accepted: 07/29/2020] [Indexed: 02/06/2023]
Abstract
Alcohol is a psychoactive substance highly used worldwide, whose harmful use might cause a broad range of mental and behavioural disorders. Underlying brain impact, the neuroinflammatory response induced by alcohol is recognised as a key contributing factor in the progression of other neuropathological processes, such as neurodegeneration. These sequels are determined by multiple factors, including age of exposure. Strikingly, it seems that the endocannabinoid system modulation could regulate the alcohol-induced neuroinflammation. Although direct CB1 activation can worsen alcohol consequences, targeting other components of the expanded endocannabinoid system may counterbalance the pro-inflammatory response. Indeed, specific modulations of the expanded endocannabinoid system have been proved to exert anti-inflammatory effects, primarily through the CB2 and PPARγ signalling. Among them, some endo- and exogeneous cannabinoids can block certain pro-inflammatory mediators, such as NF-κB, thereby neutralizing the neuroinflammatory intracellular cascades. Furthermore, a number of cannabinoids are able to activate complementary anti-inflammatory pathways, which are necessary for the transition from chronically overactivated microglia to a regenerative microglial phenotype. Thus, cannabinoid modulation provides cooperative anti-inflammatory mechanisms that may be advantageous to resolve a pathological neuroinflammation in an alcohol-dependent context.
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Affiliation(s)
- Alba García-Baos
- Neurobiology of Behaviour Research Group (GReNeC-NeuroBio), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Laia Alegre-Zurano
- Neurobiology of Behaviour Research Group (GReNeC-NeuroBio), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Lídia Cantacorps
- Neurobiology of Behaviour Research Group (GReNeC-NeuroBio), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Ana Martín-Sánchez
- Neurobiology of Behaviour Research Group (GReNeC-NeuroBio), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain; Neuroscience Research Programme, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
| | - Olga Valverde
- Neurobiology of Behaviour Research Group (GReNeC-NeuroBio), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain; Neuroscience Research Programme, IMIM-Hospital del Mar Research Institute, Barcelona, Spain.
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Levitt DE, Yeh AY, Prendergast MJ, Budnar, Jr. RG, Adler KA, Cook G, Molina PE, Simon L. Chronic Alcohol Dysregulates Skeletal Muscle Myogenic Gene Expression after Hind Limb Immobilization in Female Rats. Biomolecules 2020; 10:E441. [PMID: 32178412 PMCID: PMC7175129 DOI: 10.3390/biom10030441] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 03/07/2020] [Accepted: 03/10/2020] [Indexed: 12/20/2022] Open
Abstract
Alcohol use and aging are risk factors for falls requiring immobilization and leading to skeletal muscle atrophy. Skeletal muscle regeneration is integral to post-immobilization recovery. This study aimed to elucidate the effects of alcohol and ovarian hormone loss on the expression of genes implicated in muscle regeneration. Three-month-old female rats received an ovariectomy or a sham surgery, consumed an alcohol-containing or control diet for 10 weeks, were subjected to unilateral hind limb immobilization for seven days, and finally were allowed a three (3d)- or 14 (14d)-day recovery. Immobilization decreased the quadriceps weight at 3d and 14d, and alcohol decreased the quadriceps weight at 14d in the nonimmobilized hind limb (NI). At 3d, alcohol decreased gene expression of myoblast determination protein (MyoD) in the immobilized hind limb (IMM) and myocyte enhancer factor (Mef)2C and tumor necrosis factor (TNF)α in NI, and ovariectomy increased MyoD and decreased TNFα expression in NI. At 14d, alcohol increased the gene expression of Mef2C, MyoD, TNFα, and transforming growth factor (TFG)β in IMM and decreased monocyte chemoattractant protein (MCP)1 expression in NI; ovariectomy increased TNFα expression in NI, and alcohol and ovariectomy together increased Mef2C expression in NI. Despite increased TGFβ expression, there was no concomitant alcohol-mediated increase in collagen in IMM at 14d. Overall, these data indicate that alcohol dysregulated the post-immobilization alteration in the expression of genes implicated in regeneration. Whether alcohol-mediated molecular changes correspond with post-immobilization functional alterations remains to be determined.
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Affiliation(s)
| | | | | | | | | | | | | | - Liz Simon
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; (D.E.L.); (A.Y.Y.); (M.J.P.); (R.G.B.J.); (K.A.A.); (G.C.); (P.E.M.)
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Zahr NM. Peripheral TNFα elevations in abstinent alcoholics are associated with hepatitis C infection. PLoS One 2018; 13:e0191586. [PMID: 29408932 PMCID: PMC5800541 DOI: 10.1371/journal.pone.0191586] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 01/08/2018] [Indexed: 12/31/2022] Open
Abstract
Substantial evidence supports the view that inflammatory processes contribute to brain alterations in HIV infection. Mechanisms recently proposed to underlie neuropathology in Alcohol Use Disorder (AUD) include elevations in peripheral cytokines that sensitize the brain to the damaging effects of alcohol. This study included 4 groups: healthy controls, individuals with AUD (abstinent from alcohol at examination), those infected with HIV, and those comorbid for HIV and AUD. The aim was to determine whether inflammatory cytokines are elevated in AUD as they are in HIV infection. Cytokines showing group differences included interferon gamma-induced protein 10 (IP-10) and tumor necrosis factor α (TNFα). Follow-up t-tests revealed that TNFα and IP-10 were higher in AUD than controls but only in AUD patients who were seropositive for Hepatitis C virus (HCV). Specificity of TNFα and IP-10 elevations to HCV infection status was provided by correlations between cytokine levels and HCV viral load and indices of liver integrity including albumin/globulin ratio, fibrosis scores, and AST/platelet count ratio. Because TNFα levels were mediated by HCV infection, this study provides no evidence for elevations in peripheral cytokines in "uncomplicated", abstinent alcoholics, independent of liver disease or HCV infection. Nonetheless, these results corroborate evidence for elevations in IP-10 and TNFα in HIV and for IP-10 levels in HIV+HCV co-infection.
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Affiliation(s)
- Natalie M. Zahr
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States of America
- Neuroscience Department, SRI International, Menlo Park, CA, United States of America
- * E-mail:
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Li W, Amet T, Xing Y, Yang D, Liangpunsakul S, Puri P, Kamath P, Sanyal A, Shah V, Katz B, Radaeva S, Crabb D, Chalasani N, Yu Q. Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study. Hepatology 2017; 66:575-590. [PMID: 28466561 PMCID: PMC5548491 DOI: 10.1002/hep.29242] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 03/27/2017] [Accepted: 04/24/2017] [Indexed: 12/13/2022]
Abstract
Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty-eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL-6], IL-8, interferon gamma-induced protein 10, IL-4, IL-9, IL-10, fibroblast growth factor 2, IL-7, IL-15, and transforming growth factor alpha) but lower levels of the anti-inflammatory macrophage-derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon-gamma in response to T-cell stimulation. Up-regulated IL-6, IL-8, CD38, and CD69 and down-regulated macrophage-derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL-6, IL-8, CD38, and CD69 were reduced, whereas levels of macrophage-derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL-8, IL-10, fibroblast growth factor 2, and IL-7 remained higher. CONCLUSION AH patients were in a highly immune-dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (Hepatology 2017;66:575-590).
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Affiliation(s)
- Wei Li
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Tohti Amet
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Yanyan Xing
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Dennis Yang
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
- Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Puneet Puri
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298
| | - Patrick Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Arun Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298
| | - Vijay Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Barry Katz
- Department of Biostatistics, Indiana University School of Medicine and Richard M. Fairbanks School of Public Health, Indianapolis, IN 46202
| | - Svetlana Radaeva
- National Institute of Alcoholism and Alcohol Abuse, National Institutes of Health, Rockville, MD
| | - David Crabb
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
- Internal Medicine, Eskenazi Health, Indianapolis, IN 46202
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
| | - Qigui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
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11
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Orellana JA, Cerpa W, Carvajal MF, Lerma-Cabrera JM, Karahanian E, Osorio-Fuentealba C, Quintanilla RA. New Implications for the Melanocortin System in Alcohol Drinking Behavior in Adolescents: The Glial Dysfunction Hypothesis. Front Cell Neurosci 2017; 11:90. [PMID: 28424592 PMCID: PMC5380733 DOI: 10.3389/fncel.2017.00090] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 03/15/2017] [Indexed: 12/12/2022] Open
Abstract
Alcohol dependence causes physical, social, and moral harms and currently represents an important public health concern. According to the World Health Organization (WHO), alcoholism is the third leading cause of death worldwide, after tobacco consumption and hypertension. Recent epidemiologic studies have shown a growing trend in alcohol abuse among adolescents, characterized by the consumption of large doses of alcohol over a short time period. Since brain development is an ongoing process during adolescence, short- and long-term brain damage associated with drinking behavior could lead to serious consequences for health and wellbeing. Accumulating evidence indicates that alcohol impairs the function of different components of the melanocortin system, a major player involved in the consolidation of addictive behaviors during adolescence and adulthood. Here, we hypothesize the possible implications of melanocortins and glial cells in the onset and progression of alcohol addiction. In particular, we propose that alcohol-induced decrease in α-MSH levels may trigger a cascade of glial inflammatory pathways that culminate in altered gliotransmission in the ventral tegmental area and nucleus accumbens (NAc). The latter might potentiate dopaminergic drive in the NAc, contributing to increase the vulnerability to alcohol dependence and addiction in the adolescence and adulthood.
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Affiliation(s)
- Juan A Orellana
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Laboratorio de Neurociencias, Departamento de Neurología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de ChileSantiago, Chile
| | - Waldo Cerpa
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Laboratorio de Función y Patología Neuronal, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileSantiago, Chile
| | - Maria F Carvajal
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Unidad de Neurociencia, Centro de Investigación Biomédica, Universidad Autónoma de ChileSantiago, Chile
| | - José M Lerma-Cabrera
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Unidad de Neurociencia, Centro de Investigación Biomédica, Universidad Autónoma de ChileSantiago, Chile
| | - Eduardo Karahanian
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Unidad de Neurociencia, Centro de Investigación Biomédica, Universidad Autónoma de ChileSantiago, Chile
| | - Cesar Osorio-Fuentealba
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Facultad de Kinesiología, Artes y Educación Física, Universidad Metropolitana de Ciencias de la EducaciónSantiago, Chile
| | - Rodrigo A Quintanilla
- Centro de Investigación y Estudio del Consumo de Alcohol en AdolescentesSantiago, Chile.,Laboratory of Neurodegenerative Diseases, Universidad Autónoma de ChileSantiago, Chile
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12
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Dasarathy S. Nutrition and Alcoholic Liver Disease: Effects of Alcoholism on Nutrition, Effects of Nutrition on Alcoholic Liver Disease, and Nutritional Therapies for Alcoholic Liver Disease. Clin Liver Dis 2016; 20:535-50. [PMID: 27373615 PMCID: PMC4934388 DOI: 10.1016/j.cld.2016.02.010] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Malnutrition is the most frequent and nearly universal consequence in alcoholic liver disease (ALD) that adversely affects clinical outcomes. Sarcopenia or skeletal muscle loss is the major component of malnutrition in liver disease. There are no effective therapies to prevent or reverse sarcopenia in ALD because the mechanisms are not well understood. Consequences of liver disease including hyperammonemia, hormonal perturbations, endotoxemia and cytokine abnormalities as well as the direct effects of alcohol and its metabolites contribute to sarcopenia in ALD. This article focuses on the prevalence, methods to quantify malnutrition, specifically sarcopenia and potential therapies including novel molecular targeted treatments.
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Affiliation(s)
- Srinivasan Dasarathy
- Departments of Gastroenterology, Hepatology and Pathobiology, Cleveland Clinic, Cleveland, Ohio
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13
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Heberlein A, Käser M, Lichtinghagen R, Rhein M, Lenz B, Kornhuber J, Bleich S, Hillemacher T. TNF-α and IL-6 serum levels: neurobiological markers of alcohol consumption in alcohol-dependent patients? Alcohol 2014; 48:671-6. [PMID: 25262503 DOI: 10.1016/j.alcohol.2014.08.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
We investigated the serum levels of IL-6 and TNF-α in 30 male alcohol-dependent patients during withdrawal (day 1, 7, and 14) and compared them with the levels obtained from 18 healthy male controls. IL-6 (day 1: T = 2,593, p = 0.013; day 7: T = 2,315, p = 0.037; day 14: T = 1,650, p = 0.112) serum levels were significantly increased at the beginning of alcohol withdrawal. TNF-α (T = 3,202, p = 0.03) serum levels were significantly elevated in the patients' group during the whole period of withdrawal. IL-6 serum levels decreased significantly during withdrawal (F = 16.507, p < 0.001), whereas TNF-α levels did not change significantly (day 1-14). IL-6 serum levels were directly associated with alcohol consumption (r = 0.392, p = 0.047) on day 1. Moreover, the IL-6 serum levels were associated with alcohol craving (PACS total score day 1: r = -0.417, p = 0.022, the score of the obsessive subscale of the OCDS on day 14 [r = -0.549, p = 0.022]), depression (r = -0.507, p = 0.005), and trait anxiety (r = -0.674, p < 0.001) on day 1. We found an association with the duration of active drinking following the last period of abstinence and the TNF-α serum levels (day 1:r = 0.354, p = 0.009; day 7: r = 0.323, p = 0.022; day 14: r = 0.303, p = 0.034) as well as an association with the severity of alcohol dependence measured by the SESA scale (r = 0.454, p = 0.015). Moreover, we found a significant association between the BDNF serum levels and the TNF-α serum levels (r = -0.426, p = 0.021). Our results support an association between alterations in TNF-α and IL-6 serum levels and alcohol consumption.
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Affiliation(s)
- Annemarie Heberlein
- Center for Addiction Research (CARe), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hanover, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany.
| | - Marius Käser
- Center for Addiction Research (CARe), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hanover, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany
| | | | - Mathias Rhein
- Center for Addiction Research (CARe), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hanover, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany
| | - Bernd Lenz
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Germany
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Germany
| | - Stefan Bleich
- Center for Addiction Research (CARe), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hanover, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany
| | - Thomas Hillemacher
- Center for Addiction Research (CARe), Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hanover, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany
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14
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González-Reimers E, Santolaria-Fernández F, Martín-González MC, Fernández-Rodríguez CM, Quintero-Platt G. Alcoholism: A systemic proinflammatory condition. World J Gastroenterol 2014; 20:14660-14671. [PMID: 25356029 PMCID: PMC4209532 DOI: 10.3748/wjg.v20.i40.14660] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Excessive ethanol consumption affects virtually any organ, both by indirect and direct mechanisms. Considerable research in the last two decades has widened the knowledge about the paramount importance of proinflammatory cytokines and oxidative damage in the pathogenesis of many of the systemic manifestations of alcoholism. These cytokines derive primarily from activated Kupffer cells exposed to Gram-negative intestinal bacteria, which reach the liver in supra-physiological amounts due to ethanol-mediated increased gut permeability. Reactive oxygen species (ROS) that enhance the inflammatory response are generated both by activation of Kupffer cells and by the direct metabolic effects of ethanol. The effects of this increased cytokine secretion and ROS generation lie far beyond liver damage. In addition to the classic consequences of endotoxemia associated with liver cirrhosis that were described several decades ago, important research in the last ten years has shown that cytokines may also induce damage in remote organs such as brain, bone, muscle, heart, lung, gonads, peripheral nerve, and pancreas. These effects are even seen in alcoholics without significant liver disease. Therefore, alcoholism can be viewed as an inflammatory condition, a concept which opens the possibility of using new therapeutic weapons to treat some of the complications of this devastating and frequent disease. In this review we examine some of the most outstanding consequences of the altered cytokine regulation that occurs in alcoholics in organs other than the liver.
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15
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Yang H, Chang J, Chen W, Zhao L, Qu B, Tang C, Qi Y, Zhang J. Treadmill exercise promotes interleukin 15 expression in skeletal muscle and interleukin 15 receptor alpha expression in adipose tissue of high-fat diet rats. Endocrine 2013; 43:579-85. [PMID: 23076740 DOI: 10.1007/s12020-012-9809-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2011] [Accepted: 09/27/2012] [Indexed: 11/29/2022]
Abstract
Interleukin 15 (IL-15) has recently been proposed as a myokine involved in regulating lipid metabolism. We investigated the effect of exercise training on IL-15 content in skeletal muscle and expression of IL-15 receptor (IL-15R) in adipose tissue of obese rats. After 12 weeks of a high-fat diet, obese rats underwent treadmill running at 26 m/min (60 min each, 5 days/week for 8 weeks). High-fat diet induced obesity, with increased body weight, body fat, and lipid profile. The level of IL-15 immunoreactivity (IL-15-ir) in plasma and gastrocnemius muscle was lower in obese than control rats, and the mRNA level of IL-15 in gastrocnemius muscle was markedly decreased. The mRNA and protein levels of IL-15R in adipose tissue were markedly lower in obese rats. Compared with sedentary obese rats, treadmill running showed decreased body weight and elevated mRNA expression of IL-15 in muscle and elevated IL-15-ir level in plasma and muscle. The mRNA and protein level of IL-15R were increased in adipose tissue in treadmill running obese rats. Our results showed that exercise training improve obesity and reversed the downregulation of the IL-15 in muscle and IL-15R in adipose tissue induced by high-fat diet.
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Affiliation(s)
- Hongtao Yang
- School of P.E. and Sports Science, Beijing Normal University, Beijing, 100875, China
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16
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Beech RD, Qu J, Leffert JJ, Lin A, Hong KA, Hansen J, Umlauf S, Mane S, Zhao H, Sinha R. Altered expression of cytokine signaling pathway genes in peripheral blood cells of alcohol dependent subjects: preliminary findings. Alcohol Clin Exp Res 2012; 36:1487-96. [PMID: 22471388 DOI: 10.1111/j.1530-0277.2012.01775.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2011] [Accepted: 12/31/2011] [Indexed: 11/30/2022]
Abstract
BACKGROUND Preclinical and clinical studies have implicated changes in cytokine and innate immune gene-expression in both the development of and end-organ damage resulting from alcohol dependence. However, these changes have not been systematically assessed on the basis of alcohol consumption in human subjects. METHODS Illumina Sentrix Beadchip (Human-6v2) microarrays were used to measure levels of gene-expression in peripheral blood in 3 groups of subjects: those with alcohol dependence (AD, n = 12), heavy drinkers (HD; defined as regular alcohol use over the past year of at least 8 standard drinks/wk for women and at least 15 standard drinks/wk for men, n = 13), and moderate drinkers (MD; defined as up to 7 standard drinks/wk for women and 14 standard drinks/wk for men, n = 17). RESULTS Four hundred and thirty-six genes were differentially expressed among the 3 groups of subjects (false discovery rate corrected p-value < 0.05). Two hundred and ninety-one genes differed between AD and MD subjects, 240 differed between AD and HD subjects, but only 6 differed between HD and MD subjects. Pathway analysis using DAVID and GeneGO Metacore(®) software showed that the most affected pathways were those related to T-cell receptor and Janus kinase-Signal transducer and activator of transcription (JAK-Stat) signaling. CONCLUSIONS These results suggest the transition from heavy alcohol use to dependence is accompanied by changes in the expression of genes involved in regulation of the innate immune response. Such changes may underlie some of the previously described changes in immune function associated with chronic alcohol abuse. Early detection of these changes may allow individuals at high risk for dependence to be identified.
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Affiliation(s)
- Robert D Beech
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06519, USA.
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