Researchers have investigated the potential bidirectional relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and sarcopenia, two conditions that often occur together but whose causal links remain unclear. The study aimed to determine whether each condition could contribute to the development of the other and to identify key molecular mediators involved in the interaction between liver and muscle.
The team used Mendelian randomization to assess whether traits related to sarcopenia, such as reduced muscle mass and function, increase the risk of MASLD. To further understand these relationships, they created various mouse models that reflect different aspects of MASLD and muscle atrophy. They also performed transcriptomic profiling on both liver and muscle tissues to analyze changes in gene expression.
According to the researchers, "Complementing prior genetic evidence establishing MASLD as a causal factor for sarcopenia, our Mendelian randomization analysis revealed that diminished muscle mass and muscle function contribute to an elevated risk of MASLD." In their mouse studies, animals with MASLD showed signs of muscle loss, decreased strength, and abnormal fat accumulation in skeletal muscles. On the other hand, mice with induced muscle atrophy experienced worse liver fat buildup, inflammation, and fibrosis when they also had MASLD.
The transcriptional data indicated that sarcopenia negatively affects liver metabolism by increasing fatty acid uptake and reducing oxidative phosphorylation. At the same time, MASLD appears to worsen muscle dysfunction through heightened inflammation and metabolic disturbances. The researchers identified C-C motif chemokine ligand 2 (CCL2) as a myokine produced by muscles that can drive MASLD progression. They also found adrenomedullin (ADM), a hepatokine released from the liver, as a trigger for sarcopenia.
"By integrating MR analysis, complementary mouse models, and multi-tissue transcriptomics, we identified CCL2 and ADM as putative mediators of this inter-organ communication," stated the authors. "These findings underscore the importance of viewing MASLD and sarcopenia as interconnected disorders, and targeting the hepatokine-myokine axis may break the vicious cycle that sustains both diseases."
The study concludes by calling for additional research to clarify when each condition develops relative to the other and to further explore how CCL2 and ADM influence disease pathways.
