Intramyocellular lipid droplet-mitochondria uncoupling drives muscle atrophy via metabolite-directed epigenetic...

Type 2 diabetes mellitus (T2DM)-associated sarcopenia is driven by protein degradation and impaired myogenic regeneration. While classical models emphasize cytosolic kinase pathways, the subcellular mechanisms mediating lipotoxicity-induced chronic catabolism remain incompletely understood. This review elucidates a tripartite pathological cascade comprising organelle structural uncoupling, metabolic intermediate overflow, and epigenetic reprogramming. Chronic intramyocellular lipid accumulation disrupts lipid droplet-mitochondria contact (LDMC) sites, largely via Mfn2 modification. This spatial dissociation impairs mitochondrial oxidation, driving the nucleocytoplasmic accumulation of polar metabolites, specifically Acetyl-CoA, succinate, and lactate. Acting as covalent substrates or competitive inhibitors, these metabolites modulate histone-modifying enzymes such as p300/CBP and JmjC-domain demethylases. Consequently, this substrate-driven epigenetic remodeling increases chromatin accessibility at E3 ubiquitin ligase promoters (Atrogin-1, MuRF1) and concurrently represses myogenic loci (MyoD, MyoG), locking the tissue in a catabolic transcriptional state. Effective interventions must target this organelle-metabolite-epigenetic axis. Beyond systemic agents like SGLT2 inhibitors and GLP-1 receptor agonists, precision strategies-including repairing LDMC topology, bypassing enzymatic bottlenecks via CPT1 or LDHA, and restoring epigenetic homeostasis-are necessary to preserve lean mass and maintain skeletal muscle under metabolic stress.