Skeletal muscle and MASLD: Mechanistic and clinical insights

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is intrinsically linked with widespread metabolic perturbations, including within skeletal muscle. Indeed, MASLD is associated with a range of skeletal muscle abnormalities, including insulin resistance, myosteatosis, and sarcopenia, which all converge on the liver to drive disease progression and adverse patient outcomes. This review explores the mechanistic links between skeletal muscle and MASLD, including the role of abnormal glycemic control, systemic inflammation, and disordered myokine signaling. In turn, we discuss how intrinsic liver pathology can feed back to further exacerbate poor skeletal muscle health. Given the central importance of skeletal muscle in MASLD pathogenesis, it offers clinicians an opportunity to intervene for therapeutic benefit. We, therefore, summarize the role of nutrition and physical activity on skeletal muscle mass, quality, and metabolic function and discuss the knock-on effect this has on the liver. An awareness of these treatment strategies is particularly important in the era of effective pharmacological and surgical weight loss interventions, which can be associated with the development of sarcopenia. Finally, we highlight a number of promising drug agents in the clinical trial pipeline that specifically target skeletal muscle in an attempt to improve metabolic and physical functioning.

Keywords: MASH; adipose; exercise; hepatokines; insulin resistance; myokines; myosteatosis; obesity; sarcopenia.

FIGURE 1

Diagnostic and assessment tools for muscle pathology in patients with MASLD. Figure created using biorender.com. Abbreviations: ALM/W, appendicular lean mass adjusted by weight; BIA, bioelectrical impedance analysis; BMI, body mass index; DEXA, dual-energy X-ray absorptiometry; EASO, European Association for the Study of Obesity; ESPEN, European Society for Clinical Nutrition and Metabolism; FI, frailty index; MASLD, metabolic dysfunction–associated steatotic liver disease; M/I value, glucose metabolism per unit of insulin; Rd, rate of glucose disposal; SWW/W, total skeletal muscle mass adjusted by weight.

FIGURE 2

Bidirectional relationship between MASLD and skeletal muscle and the impact of exercise on pathogenic pathways and liver histology. Skeletal muscle insulin resistance, myosteatosis, and sarcopenia all converge on the liver to drive the progression of MASLD. Reciprocally, multiple pathways feed back from the liver to influence the function, quality, and quantity of skeletal muscle. Both aerobic and resistance exercises have widespread benefits in all 3 domains of muscle pathology. Exercise is also able to improve steatosis and reduce surrogate markers of fibroinflammation. Further rigorous, well-controlled clinical trials are required to definitively establish the effect of exercise on liver fibrosis. Abbreviations: ANGPTL3, angiopoietin-like protein 3; ASCs, adipose stromal cells; DNL, de novo lipogenesis; HFREP1, hepatocyte-derived fibrinogen-related protein 1; LCET2, leukocyte cell–derived chemotaxin 2; MASH, metabolic dysfunction–associated steatohepatitis; MASLD, metabolic dysfunction–associated steatotic liver disease; NEFA, nonesterified fatty acids; TLR, toll-like receptor.