Increased quadriceps intermuscular adipose tissue in chronic liver disease is associated with an altered muscle transcriptome compared with healthy age matched controls

Muscle fat infiltration (i.e., myosteatosis) is an important index of muscle health and pathology in disease states, such as chronic liver disease (CLD). However, it is unknown whether myosteatosis differs due to anatomical location. Further, the mechanistic implications of divergent intermuscular adipose tissue (IMAT) deposition remain unknown in patients with CLD. Thirty-three patients with CLD (55.0 ± 10.5 years) and 17 healthy controls (HC) (49.6 ± 15.4 years) were recruited. Quadriceps IMAT was estimated between 20 and 80% of muscle length and psoas IMAT at L3 via MRI. Body composition, muscle strength, and habitual activity were assessed. Fasted vastus lateralis muscle biopsies were collected and subjected to RNA sequencing analysis. ClinicalTrials.gov identifier: NCT04734496. IMAT was greater in CLD compared with HC in both quadriceps and psoas (P < 0.0001). Quadriceps IMAT positively correlated with BMI (r = 0.62), body fat (r = 0.65), age (r = 0.36), and negatively correlated with maximal knee extensor strength (r = −0.45) and habitual physical activity (r = −0.50) in CLD and HC. One hundred sixty-nine differentially expressed genes (DEGs) were identified in low IMAT CLD vs. HC, and 178 DEGs were identified in high IMAT CLD vs. HC. CLD patients with high and low IMAT exhibited defined expression profiles, with only 39 DEGs (representing 12.7%) in common. Pathway analysis of DEGs revealed enrichment of atrophic and pro-inflammatory pathways in the high IMAT group. IMAT is greater in patients with CLD compared to HC, irrespective of anatomical location, and is associated with reductions in muscle function and may be exacerbated by physical inactivity. IMAT appears to alter the muscle transcriptome in COLD, potentially exacerbating muscle loss.