Sarcopenia and metabolic dysfunction-associated steatotic liver disease: The role of exercise-related biomarkers

Abstract

The etiology, risk factors, and management of sarcopenia and metabolic dysfunction-associated steatotic liver disease (MASLD) are comparable, which prompted the investigators to search for a particular diagnostic or prognostic biomarker that was involved in both disorders. Peptides or proteins known as myokines, or exerkines, are produced and secreted by contracted muscles. Myokines work similarly to hormones in their actions. One common clinical hallmark of sarcopenia and MASLD is physical inactivity, which is associated with alterations in the levels of myokines. Irisin is a positive regulator of muscle size that is elevated in the biological fluids during exercise. Significantly low levels were observed in the pathological conditions associated with physical inactivity. The serum levels of irisin are significantly higher in MASLD patients, while their levels were lower in risk factors of MASLD, e.g., diabetes mellitus, obesity, and insulin resistance. In sarcopenia with obesity (sarcopenic obesity) or with a normal build, serum irisin levels are significantly lower than in healthy subjects. Therefore, serial determination of irisin levels that showed a transition from higher to lower levels in MASLD indicated the development of sarcopenia in those patients.

Key Words: Sarcopenia; Metabolic dysfunction-associated steatotic liver disease; Physical inactivity; Myokines; Irisin

Core Tip: Sarcopenia and metabolic dysfunction-associated steatotic liver disease (MASLD) share similar risk factors, pathophysiology, and cause (physical inactivity). In both conditions, physical inactivity is a remarkable clinical finding. Determination of irisin in the biological fluids serves as a good marker for physical activity as it elevates during muscle contraction. In sarcopenia, serum irisin declined, while in MASLD it increased. Therefore, a transition of serum irisin from higher to lower levels in MASLD could indicate the occurrence of sarcopenia.

TO THE EDITOR

I read with great interest an elegant review published recently by Wong and Yuan[1], who highlighted the similarities of the risk factors, physiopathology, and physical inactivity in both pathological conditions. I will add to this article the role of exercise-related hormones or myokines as biomarkers of physical activity, which are involved in the bidirectional relationship between sarcopenia and metabolic dysfunction-associated steatotic liver disease (MASLD). The measurement of circulating myokines could help us determine whether sarcopenia is associated with MASLD or vice versa. Therefore, determining the circulating myokine levels in MASLD patients could be a useful additive diagnostic tool for sarcopenia. The interrelationship between obesity, MASLD, and sarcopenia is linked with physical inactivity.

RELATIONSHIP BETWEEN SERUM IRISIN LEVELS AND THE DEVELOPMENT OF SARCOPENIA IN MASLD

Physical activity could delay the progression but does not prevent sarcopenia by overcoming the dysfunction of myokines, which aggravates or causes sarcopenia[2]. Myokines, also known as exerkines, are exercise-related hormones and are defined as proteins or peptides produced and released from contracted muscles that exert autocrine, paracrine, and endocrine function. For that reason, their names are linked to the exercise-related hormones. These myokines have different effects on muscle growth or repair and are generally classified as positive or negative regulators of muscle size (Table 1).

Table 1 Classification of myokines according to their effects on muscle growth, differentiation and repair.

Positive regulators	Negative regulators
Irisin	Growth differentiation factor 8 (myostatin)
Insulin growth factor 1	Transforming growth factor β
Follistatin	Activins
Bone-morphogenic proteins	-
Brain-derived neurotrophic factor	-
Meteorin like factor (metrnl)	-
Fibroblast growth factor 21	-
Β-aminoisobutyric acid	-
Apelin	-
Interleukin 10	Interleukin 6
Interleukin 15	-

From the physiological point of view, physical activity regulates the expression of myokines, and their circulating levels will alter in diseases associated with physical inactivity such as sarcopenia or MASLD. Therefore, their determination in the circulation could be applied as physical activity indices. In both MASLD and sarcopenia, obesity and diabetes mellitus with or without complications were associated risk factors and interrelated with physical inactivity[3].

During muscle contraction, the proliferator-activated receptor gamma, coactivator 1 alpha protein is activated, leading to the upregulation of the expression of the fibronectin-III domain (domain-containing protein 5), which is cleaved at the N-terminal to release irisin through activation of different pathways, e.g., adenosine monophosphate-activated protein kinase. During physical activity, myocytes secrete irisin, which converts the white fat to brown fat, increasing exercise energy expenditure.

In the normal population, serum irisin levels are significantly associated with females, markers of inflammation, and high-density lipoprotein[4]. Lower levels are associated with aging, hypertension, obesity, diabetes mellitus, etc[5]. The peak level of irisin is observed 3-60 min after acute exercise and gradually declines to the baseline after 6 h. In chronic exercise ranging from 6 weeks to 1 year, there are no significant changes in the irisin level[6,7]. In addition, resistance exercises rather than endurance exercises are associated with higher irisin release[8].

Low serum irisin (< 118.0 ng/mL) is a predictor of sarcopenia, and it could be a useful diagnostic marker of sarcopenia[9]. Another study found higher circulating levels of irisin disease-related malnutrition without sarcopenia (651.3 ± 221.3 pg/mL), while the myostatin levels do not show a significant difference between non-sarcopenia and sarcopenia[10]. Few studies demonstrated the role of myostatin in causing muscle atrophy in obese and insulin-resistant patients[11].

In type 2 diabetes mellitus (T2DM), the circulating level of irisin is significantly lower in sarcopenia (10.7 ± 6.17 ng/mL) and sarcopenic obesity (SO) (7.66 ± 5.27 ng/mL) in sarcopenia compared with non-sarcopenia (13.67 ± 9.07 ng/mL). It is significantly and inversely correlated with the ratio of fat mass to fat-free mass (an index of SO). A cutoff value of 9.49 ng/mL is a predictor of SO in T2DM[12]. The prevalence of sarcopenia in nonalcoholic fatty liver disease (NAFLD) ranges from 1.6%-63, and it is associated with a higher risk of steatohepatitis, insulin resistance, progression of liver fibrosis, and cardiovascular events[13].

Patients with NAFLD have significantly higher serum irisin levels compared with the corresponding subjects without NAFLD (5.89 ± 3.53 μg/mL vs 4.53 ± 2.62 μg/mL, P < 0.01). The odds for NAFLD are increased by 1.17 times for each 1 μg/mL increment of irisin concentration[14]. Another study found that the median (interquartile) serum irisin level is significantly higher in NAFLD compared with the control: 5.7 (4.6-6.5) vs 7.5 (6.5-9.08) μg/mL[15]. Despite the technology used in the determination of serum irisin, it is significantly higher in NAFLD than in normal controls (63.4 ± 32.6 vs 43.0 ± 29.7 ng/mL, P < 0.001)[16].

Sarcopenia is a risk factor for NAFLD or its progression, regardless of the presence of obesity, insulin resistance, or metabolic syndrome[17,18]. Several mechanisms are shared in sarcopenia and NAFLD, including physical inactivity, insulin resistance, inflammation, dysregulation of myokines, hormonal imbalance, and nutritional deficiency[19]. T2DM accelerates the development of sarcopenia in aged subjects, and it is a risk factor for SO[20,21]. Irisin is a positive regulator of muscle growth and insulin sensitivity[22,23]. Therefore, the serum irisin levels are decreased in T2DM with poor glucose control or metabolic derangement, as with metabolic syndrome[24].

Patients with low irisin levels are at risk for insulin resistance[12], and physical inactivity is the main cause of the low irisin level, which is a cause of the loss of muscle mass and the occurrence of sarcopenia[25]. In addition, it has been reported that sarcopenia is an independent risk factor of new-onset T2DM in non-obese elderly subjects[26]. The mean ± SD of serum irisin levels in elderly patients with T2DM is significantly lower than in healthy subjects (703.37 ± 241.51 ng/mL vs 800.22 ± 275.59 ng/mL)[27].

Irisin is involved in the pathogenesis of MASLD by improving the progression of liver fibrosis via different mechanisms on the hepatic stellate cells, including regulation of their activity, proliferation, and cytokine production[28,29]. During the progression of NAFLD, the serum irisin level showed variations. For example, it is higher in mild compared with moderate-severe NAFLD[16] and significantly higher in stage ≥ 2 compared with stage 1 liver fibrosis associated with NAFLD (median value: 5.96 vs 2.42 ng/mL)[30].

Therefore, to elucidate the importance of determining the irisin level in sarcopenia associated with MASLD, the serial determination of serum irisin showed a transition from higher levels of irisin in MASLD to decreasing levels in sarcopenia-associated MASLD in elderly patients with or without risk factors including T2DM and obesity (Figure 1). In addition, it is necessary to adjust the confounder variables and the disease-related sarcopenia when calculating the irisin cutoff value in MASLD and sarcopenia, as there are wide variations in the circulating irisin levels in the reported studies. The clinical implementation of the determination of serum irisin can be utilized in managing people with a low serum irisin level, e.g., sarcopenia. Experimental studies showed that using exogenous irisin increases muscle weight and strength and improves abnormalities in the skeletal muscle in pathological conditions[31,32].

Figure 1 Bidirectional relationship between sarcopenia and metabolic dysfunction-associated steatotic liver disease in reference to circulating irisin level.

CONCLUSION

The time of addressing MASLD and sarcopenia could be supplemented by serial determination of serum irisin levels in MASLD, and a transition from higher to lower levels of irisin could predict the occurrence of sarcopenia despite the presence of risk factors like T2DM or obesity that could act as confounding factors in the interpretation of serum irisin levels. Confounding factors (e.g., age, gender, obesity, smoking, etc.) and the progression of MASLD to liver fibrosis should be considered in the interpretation of the transition of serum irisin levels between MASLD and sarcopenia to eliminate the limitations of the study.