Harnessing Muscle–Liver Crosstalk to Treat Nonalcoholic Steatohepatitis

Abstract

Non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions, affecting an estimated one-quarter of the world’s adult population. Multiple organ systems have been implicated in the pathophysiology of NAFLD; however, the role of skeletal muscle has until recently been largely overlooked. A growing body of evidence places skeletal muscle—via its impact on insulin resistance and systemic inflammation—and the muscle-liver axis at the center of the NAFLD pathogenic cascade. Population-based studies suggest that sarcopenia is an effect-modifier across the NAFLD spectrum in that it is tightly linked to an increased risk of non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), and advanced liver fibrosis, all independent of obesity and insulin resistance. Longitudinal studies suggest that increases in skeletal muscle mass over time may both reduce the incidence of NAFLD and improve preexisting NAFLD. Adverse muscle composition, comprising both low muscle volume and high muscle fat infiltration (myosteatosis), is highly prevalent in patients with NAFLD. The risk of functional disability conferred by low muscle volume in NAFLD is further exacerbated by the presence of myosteatosis, which is twice as common in NAFLD as in other chronic liver diseases. Crosstalk between muscle and liver is influenced by several factors, including obesity, physical inactivity, ectopic fat deposition, oxidative stress, and proinflammatory mediators. In this perspective review, we discuss key pathophysiological processes driving sarcopenia in NAFLD: anabolic resistance, insulin resistance, metabolic inflexibility and systemic inflammation. Interventions that modify muscle quantity (mass), muscle quality (fat), and physical function by simultaneously engaging multiple targets and pathways implicated in muscle-liver crosstalk may be required to address the multifactorial pathogenesis of NAFLD/NASH and provide effective and durable therapies.

Muscle fat content is strongly associated with NASH: A longitudinal study in patients with morbid obesity

“…40 A causal link cannot be inferred from the present analysis; however, it is tempting to speculate that a high-fat content contributes to NAFLD progression: peripheral insulin resistance and/or perturbation of the muscle metabolism and secretome associated with muscle fat 14,41,42 may promote liver inflammation and hepatocellular injury. 6,12,[14][15][16] Further studies in preclinical models, in which we showed that muscle fat infiltration (but not sarcopenia) was specifically associated with NASH, 43 will clarify the exact nature and directionality of the muscleliver axis in NAFLD progression and potentially unravel new relevant therapeutic targets.…”

“…18 Thus, patients with obesity are more likely to be categorized as sarcopenic when applying weight or BMI-based muscle mass scaling, as used in the majority of sarcopenia studies in NAFLD. [7][8][9][10][11][12][13]15,16 Moreover, high BMI per se is a well-known risk factor for NAFLD. 1 Hence, to find a low relative muscle mass in patients with NAFLD is not a surprise.…”

“…[4][5][6] Literature suggests that low muscle mass and/or low muscle strength are associated with NAFLD severity. [7][8][9][10][11][12][13][14][15][16] However, these studies suffer from limitations, including the lack of a gold standard methodology for muscle mass evaluation (i.e. CT or MRI) 17 and for NAFLD staging (liver biopsy).…”

Diet and exercise reduce pre-existing NASH and fibrosis and have additional beneficial effects on the vasculature, adipose tissue and skeletal muscle via organ-crosstalk

“…Skeletal muscle has been recognized as a vital organ for whole body metabolism, since it is a primary site for glucose uptake and storage, and it is also a reservoir of amino acids stored as protein [60]. However, recent studies have shown that sarcopenia, the loss of muscle mass and function, is a novel risk factor for developing NASH and muscle, and via its impact on insulin resistance and systemic inflammation, can be of importance in NASH pathogenesis [61,62]. Not only low muscle mass, but also an adverse muscle composition comprising a high muscle fat infiltration (myosteatosis) is associated with the severity of NASH [38].…”

Insights into Nonalcoholic Fatty-Liver Disease Heterogeneity

“…Several studies have underscored that sarcopenia (i.e., decreased muscle mass) or adverse muscle composition (i.e., low muscle volume and muscle fat infiltration or myosteatosis) may influence both NAFLD development and progression. [66][67][68] Although important methodological differences exist across published studies, not all patients with NAFLD exhibit muscle alterations and it is likely that this pathogenic factor be more relevant in particular populations, such as nonobese or lean NAFLD, as well as older patients in which sarcopenia is more frequent. 69 Activation of the innate immune system has been implicated in NAFLD progression.…”