Inlay

Dysferlinopathy is an age-dependent muscular dystrophy caused by loss of the membrane-associated protein dysferlin. Disease severity increases with age and selectively affects specific muscle groups, yet the molecular basis for this vulnerability remains unclear. Since lipid remodeling is a hallmark of dysferlinopathy and aging, we investigated how age, sex, and muscle fiber type interact to shape the muscle lipidome in dysferlin-deficient mice. We performed omics-scale lipid profiling across 738 lipid species and 30 lipid classes in quadriceps and gastrocnemius (fast-twitch muscles exhibiting pronounced pathology), soleus (slow-twitch) and extensor digitorum longus (EDL; fast-twitch, relatively spared) muscles from male and female dysferlin-deficient (BLA/J) and wildtype C57BL/6J (WT) mice aged 3, 10, and 26 months. Normal aging was associated with broad lipid remodeling, however, in the absence of dysferlin markedly amplified this remodeling, leading to elevations in specific triglycerides, diglycerides, cholesterol esters, gangliosides, ceramides, and sphingomyelin compared to WT muscle. Interestingly, we observed minimal sex differences between dysferlin-deficient muscles. Fast-twitch muscles, particularly quadriceps and gastrocnemius, exhibited the most extensive lipid alterations, whereas the slow-twitch soleus muscle showed relative lipid stability even at advanced age. Thus, fast-glycolytic muscles are more susceptible to age- and dysferlin-dependent lipid dysregulation than slow oxidative muscle. The preferential vulnerability of fast-twitch muscles to muscle wasting in dysferlinopathy suggests that fiber-type-dependent lipid handling contributes to selective muscle degeneration. This work defines a comprehensive lipidomic signature of disease progression and provides a framework for understanding how aging, sex, and muscle phenotype interact in muscular dystrophy.