The "Mechano-Metabolic-Immune" crosstalk within the skeletal muscle microenvironment: evolution of homeostatic...

Skeletal muscle functions not only as a mechanical apparatus for locomotion but also serves as a pivotal metabolic hub and endocrine organ essential for systemic homeostasis. While traditional perspectives focused on macro-volumetric measurements, contemporary biology posits that muscle quality is fundamentally an integration of mechanotransduction, biochemical metabolism, and ultrastructural coupling. Under comorbidity conditions, the progressive decline of skeletal muscle is intricately linked to multi-systemic dysfunction. In chronic inflammatory environments, mechanical imbalance and metabolic derangements are not merely additive; instead, they construct a sophisticated "mechano-metabolic-immune" network by co-regulating immune cell phenotypes and inflammatory thresholds. Pathological remodeling represents the destabilization of this homeostatic axis: lipotoxic metabolic stress induces the phenotypic deviation of fibro-adipogenic progenitors (FAPs) and M1 polarization of macrophages, establishing a pro-inflammatory priming state. Furthermore, the leakage of mitochondrial DNA (mtDNA) resulting from impaired mitochondrial quality control amplifies local metabolic disturbances into cGAS-STING pathway activation that secondary drives macrophage M1 polarization, serving as a critical driver of muscle atrophy. Within this pathological context, mechanical signals act not only as physical stimuli but as active variables that remodel microenvironmental stability. Through molecular transducers such as Piezo1, FAK, and TRPV4, kinetic loading facilitates mechano-chemical transduction and activates the energy sensor AMPK, thereby maintaining mitochondrial dynamic equilibrium and suppressing inflammatory cascades. This metabolic remodeling promotes the transition of macrophages toward a pro-regenerative/anti-inflammatory phenotype, supporting functional maintenance by resolving chronic inflammation and restoring tissue homeostasis. This review proposes the "mechano-metabolic-immune" axis as a pivotal regulatory framework governing skeletal muscle quality. Given that the biological benefits of mechanical intervention are constrained by physiological thresholds, precisely defining exercise load parameters across diverse pathological backgrounds is a rational foundation for transitioning from macro-rehabilitation to mechanism-driven precision interventions targeting FAPs adipogenic differentiation, intramuscular fat accumulation, and AMPK-mediated mitochondrial quality control, providing essential criteria for developing safe and effective clinical exercise prescriptions.