Skeletal muscle fiber-type switching, myopathy, and exercise intolerance in Sigmar1 null mice

Abstract Sigmar1 is a widely expressed, multitasking molecular chaperone protein playing functional roles in several cellular processes. Mutations in the Sigmar1 gene have been reported to associate with several motor neuropathies, including amyotrophic lateral sclerosis, distal hereditary motor neuropathy, silver-like syndrome, and frontotemporal lobar degeneration. All these human mutations associated with motor neuropathies show strong manifestation in skeletal muscle with phenotypes like muscle wasting and atrophy. However, the physiological function of Sigmar1 in skeletal muscle remains unexplored. Here, we determined the physiological role of Sigmar1 in skeletal muscle structure and function in five different skeletal muscles: gastrocnemius (Gastro), quadriceps (Quad), soleus (Sol), extensor digitorum longus (EDL), and tibialis anterior (TA). Quantification of myofiber cross-sectional area (CSA) showed altered muscle mass and a slow-to-fast fiber-type switch in the skeletal muscle fibers of the Sigmar1−/− mice. Interestingly, ultrastructural analysis by transmission electron microscopy showed the presence of tubular aggregates in the type I myofibers (Gastro, Quad, and TA) of Sigmar1−/− mice. Immunostaining also showed derangements in dystrophin localization in skeletal muscles from Sigmar1−/− mice. Additionally, skeletal muscle myopathy in Sigmar1−/− mice was associated with an increased number of central nuclei, increased collagen deposition, and fibrosis. Functional studies also showed reduced endurance and exercise capacity in the Sigmar1−/− mice. Overall, our studies demonstrated, for the first time, a potential physiological function of Sigmar1 in the skeletal muscle in maintaining healthy muscle structure and function.