Metabolic dysfunction-associated steatotic liver disease: A story of muscle and mass

Abstract

Skeletal muscle alterations (SMA) are increasingly recognized as both contributors and consequences of metabolic dysfunction-associated steatotic liver disease (MASLD), affecting disease progression and outcomes. Sarcopenia is common in patients with MASLD, with a prevalence ranging from 20% to 40% depending on the population and diagnostic criteria used. In advanced stages, such as metabolic dysfunction-associated steatohepatitis and fibrosis, its prevalence is even higher. Sarcopenia exacerbates insulin resistance, systemic inflammation, and oxidative stress, all of which worsen MASLD. It is an independent risk factor for fibrosis progression and poor outcomes including mortality. Myosteatosis refers to the abnormal accumulation of fat within muscle tissue, leading to decreased muscle quality. Myosteatosis is prevalent (> 30%) in patients with MASLD, especially those with obesity or type 2 diabetes, although this can vary with the imaging techniques used. It reduces muscle strength and metabolic efficiency, further contributing to insulin resistance and is usually associated with advanced liver disease, cardiovascular complications, and lower levels of physical activity. Altered muscle metabolism, which includes mitochondrial dysfunction and impaired amino acid metabolism, has been reported in metabolic syndromes, including MASLD, although its actual prevalence is unknown. Altered muscle metabolism limits glucose uptake and oxidation, worsening hyperglycemia and lipotoxicity. Reduced muscle perfusion and oxygenation due to endothelial dysfunction and systemic metabolic alterations are common in MASLD associated with comorbidities, such as obesity, hypertension, and atherosclerosis. It decreases the muscle capacity for aerobic metabolism, leading to fatigue and reduced physical activity in patients with MASLD, aggravating metabolic dysfunction. Various SMA in MASLD worsen insulin resistance and hepatic fat accumulation, may accelerate progression to fibrosis and cirrhosis, and increase the risk of cardiovascular disease and mortality. Management strategies for SMA include resistance training, aerobic exercise, and nutritional support (e.g., high-protein diets, vitamin D, and omega-3 fatty acids), which are essential for mitigating skeletal muscle loss and improving outcomes. However, pharmacological agents that target the muscle and liver (such as glucagon-like peptide-1 receptor agonists) show promise but have not yet been approved for the treatment of MASLD.

Keywords: Metabolic dysfunction-associated steatotic liver disease; Skeletal muscle alterations; Sarcopenia; Skeletal muscle mass index; Myosteatosis; Dietary patterns; High-protein diet; Physical activity; Glucagon-like peptide-1 receptor agonists

Core Tip: Skeletal muscle alterations, such as sarcopenia, myosteatosis, and altered muscle metabolism, are highly prevalent in metabolic dysfunction-associated steatotic liver disease (MASLD) and are increasingly recognized as both contributors and consequences of MASLD, affecting disease progression and outcomes. Common treatment approaches for both conditions include nutritional interventions and physical activity/exercise aimed at increasing insulin sensitivity and reducing fat mass but maintaining muscle mass and function. Pharmacological agents that target the muscle and liver (such as glucagon-like peptide-1 receptor agonists) show promise, but have not yet been approved for the treatment of MASLD.