Sex-dimorphic DNA lesion accumulation drives a PDK4 metabolic checkpoint in skeletal muscle

Skeletal muscle loss and functional decline are sexually dimorphic, with fast-twitch type II fibers disproportionately vulnerable to age-related atrophy. DNA damage accumulation is a hallmark of aging whose consequences in myofibers remain poorly understood. Using a type II fiber-specific DNA repair-deficient mouse, we show that the same genotoxic insult produces qualitatively different lesion landscapes by sex, oxidative damage in females and uracil misincorporation in males. Females exhibited greater atrophy pathway activation, paralleling clinical evidence that genotoxic stress disproportionately drives frailty in women. Single- nucleus RNA sequencing and metabolomics identified PDK4 as the key female-specific metabolic driver. Pharmacologic PDK4 inhibition restored oxidative metabolism and myotube health. Dietary α-ketoglutarate, replenishing TCA intermediates downstream of the PDK4 block, rescued contractile force and metabolic profiles in females. Human aging data confirmed conservation of this pathway, revealing a sex-specific mechanism linking DNA damage to metabolic dysfunction and identifying an accessible therapeutic strategy to combat female-predominant frailty.