Sarcopenia often co-occurs with obesity and insulin resistance in humans, yet it remains unclear whether skeletal muscle dysfunction reflects primary muscle pathology or arises secondary to systemic metabolic stress. We hypothesized that metabolic dysfunction originating in the liver and adipose tissue suppresses skeletal muscle gene regulatory capacity through chromatin-level repression rather than through muscle-intrinsic inflammatory activation. To test this, we performed integrated cross-tissue RNA sequencing of liver, adipose tissue, and skeletal muscle from genetically diverse CC-RIX mice exposed to a high-fat, high-sugar (HFHS) diet with and without metformin treatment. Differential expression and pathway enrichment analyses were used to define tissue-specific and systemic transcriptional responses to metabolic stress. HFHS diet induced extensive transcriptional remodeling in the liver, including disruption of metabolic and mitochondrial pathways, and robust activation of inflammatory and lipid-associated pathways in adipose tissue. In contrast, skeletal muscle exhibited a markedly constrained transcriptional response, with enrichment analyses revealing coordinated downregulation of chromosome organization and gene regulatory pathways, consistent with chromatin repression and reduced transcriptional adaptability. Gene-level overlap across tissues was minimal, underscoring the strong tissue specificity of metabolic stress responses. Metformin treatment substantially attenuated HFHS-induced pathway dysregulation in liver and adipose tissue but exerted limited direct transcriptional effects in skeletal muscle. These findings support a physiologically relevant model in which sarcopenia associated with insulin resistance emerges secondary to systemic metabolic and inflammatory stress rather than primary muscle-intrinsic dysfunction, identifying chromatin repression as a key molecular feature linking metabolic disease to skeletal muscle decline. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Agbonifo-Chijiokwu et al. (Fri,) studied this question.