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.

Keywords: NASH; adipose tissue; inflammation; insulin resistance; lipotoxicity; myosteatosis; obesity; skeletal muscle.

Figure 1

Definition, sequelae, and related comorbidities of sarcopenia. Diagnosis includes assessment of both muscle mass and strength with functional impairments seen across multiple domains; sarcopenia is associated with nearly every major chronic disease.

Figure 2

The role of the muscle-liver axis in sarcopenia and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). Recent evidence in the context of NAFLD and NASH, such as that from Kim et al (49). offers compelling associations between changes in skeletal muscle index (SMI) and both NAFLD incidence and resolution of existing NAFLD. In this longitudinal study, these marked associations persisted for the highest tertile of SMI change over 1 year, relative to the lowest tertile, even after full adjustments for multiple covariates including baseline SMI.

Figure 3

The role of muscle composition in non-alcoholic fatty liver disease (NAFLD) and related comorbidities. A recent analysis of the UK-BioBank (UKBB) resource by Linge et al (69). revealed that participants with NAFLD and normal muscle composition had generally similar metabolic and functional characteristics to those with normal liver and muscle composition. Interestingly, participants with NAFLD combined with adverse muscle composition (AMC), defined as the presence of both low muscle volume (i.e., <25th percentile of the UKBB population) and high muscle fat infiltration (i.e., >75th percentile of the UKBB population), exhibited a larger “footprint” (higher prevalence) of relevant comorbidities and functional impairment when compared with the other groups evaluated. Numbers on axes represent prevalence (%) of each indicated comorbidity/functional impairment.

Figure 4

Key mechanisms and molecular signals that link sarcopenia and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The complex interorgan crosstalk between liver and muscle likely shares a number of key underlying mechanisms, many of which relate both sarcopenia and NAFLD/NASH to metabolic stress, cascading to biochemical pathways that impact systemic insulin resistance, inflammation/oxidative stress, and anabolic resistance. Among these mechanisms are a number of existing or emergent predisposing factors and the release of multidirectional molecular signals consisting of myokines, hepatokines, and adipokines. In the context of sarcopenia, skeletal muscle could exert dysregulated influence on the muscle-liver axis to potentially play a causative role in NAFLD incidence or progression. DNL, de novo lipogenesis; FABP, fatty acid-binding protein; FAO, fatty acid oxidation; FFA, free fatty acid; FGF21, fibroblast growth factor 21; HPS, hepassocin; IL-6, interleukin-6; LECT2, leukocyte cell-derived chemotaxin-2; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-alpha.

Figure 5

Metabolic inflexibility in non-alcoholic steatohepatitis (NASH). Continuous respiratory quotient (RQ) evaluations in a whole-room calorimetry study revealed less efficient biofuel switching, i.e., metabolic inflexibility, among subjects with NASH cirrhosis compared with non-NASH cirrhosis, manifesting as a delayed time to peak RQ in a fed state, and an inability to switch to lower RQ in a fasted state. These findings reflect an impaired ability of skeletal muscle to utilize fatty acids for oxidation in the fasted state in subjects with NASH cirrhosis. [Adapted from Siddiqui et al (116). Copyright 2019, with permission from Wiley.].