The Repair Tax of Resistance Training: Microdamage Control as a Molecular Gatekeeper of Hypertrophy

Resistance exercise (RE) is a potent hypertrophic stimulus for skeletal muscle but simultaneously imposes mechanical strain that induces focal microdamage within the sarcomeric force-transmission network. This review synthesizes evidence describing how early, damage-driven cytoskeletal repair responses establish the structural basis for effective hypertrophic remodeling in repeatedly RE-stimulated human skeletal muscle. We integrate literature at the intersection of muscle damage, proteostatic regulation, and human adaptation to RE, highlighting molecular damage control as a central yet underappreciated component of resistance training adaptation. Particular emphasis is placed on chaperone-assisted selective autophagy (CASA) and the small heat shock protein αB-crystallin (CRYAB), key regulators of proteostasis in mechanically stressed muscle. We outline mechanisms governing muscle anabolism and catabolism, the structural localization of RE-induced microdamage, and acute mechanoprotective programs involving CASA and small heat shock proteins. We propose that microlesions function as focal signaling hubs linking mechanical strain to transcriptional control via a CRYAB–SMAD4 axis. Following intense or unfamiliar RE, rapid CRYAB phosphorylation stabilizes strained cytoskeletal proteins and supports BAG3-dependent turnover, while spatial mTORC1 modulation enables localized autophagy alongside preserved protein synthesis. With repeated training, cytoskeletal reinforcement reduces lesion burden and shifts remodeling toward net myofibrillar accretion, informing mechanistically grounded RE program design.