Impairment of Physiological Function in Skeletal Muscle from Sigmar1 Knockout Mice

Abstract

Rationale Sigmar1 is a widely expressed, multitasking molecular chaperone protein shown to play an important role in several vital cellular processes. Sigmar1 is encoded by SIGMAR1 gene, and mutations in this gene have been linked to several motor neuropathies, including distal hereditary motor neuropathy, amyotrophic lateral sclerosis, 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. Objectives We focus on determining the physiological role of Sigmar1 in skeletal muscle structure and function. Methods and Results We first confirmed the mRNA and protein expression of Sigmar1 where different types of skeletal muscle, including gastrocnemius (Gastro), quadriceps (Quad), soleus (Sol), extensor digitorum longus (EDL), and tibialis anterior (TA) isolated from wildtype (Wt) mice showing a differential expression of Sigmar1 in different types of skeletal muscles. Morphometric analysis of different skeletal muscle isolated from Wt and Sigmar1 global knockout (Sigmar1-/-) mice showed a similar weight-to-tibia length ratio across the group in all these muscles. Quantification of myofiber cross-sectional area (CSA) showed Gastro and Quad muscles isolated from Sigmar1-/- mice had larger muscle mass whereas TA, Sol, and EDL from Sigmar1-/- mice had smaller CSA compared to those from Wt mice. We also observed a slow-to-fast fiber-type switch in the skeletal muscle fibers from the Sigmar1-/- mice. Interestingly, ultrastructural analysis by transmission electron microscopy of skeletal muscles from Sigmar1-/- mice showed the presence of tubular aggregates in the Gastro and TA muscles. We also observed derangement in dystrophin localization in skeletal muscles from Sigmar1-/- mice. Additionally, skeletal muscles from Sigmar1-/- mice showed an increased number of central nuclei H&E staining), increased collagen deposition (Picro-Sirius red staining), and fibrosis (Masson's trichrome staining). Functional studies via measurement of grip strength and treadmill exercise showed Sigmar1-/- to have reduced endurance and exercise capacity compared to Wt mice. Conclusions Overall, our studies demonstrate a potential physiological function of Sigmar1 in the skeletal muscle in maintaining healthy muscle structure and function.