The Physiological Function of Sigmar1 in the Skeletal Muscle in Mice

Abstract

RationaleSigmar1 is an abundantly expressed molecular chaperone protein encoded by the SIGMAR1 gene. Mutations in SIGMAR1 have been associated with distal hereditary motor neuropathy, amyotrophic lateral sclerosis, silver‐like syndrome, and frontotemporal lobar degeneration. All these human mutation associated pathologies show skeletal muscle phenotypes like muscle wasting and atrophy. However, the physiological function of Sigmar1 in skeletal muscle has not been explored yet.ObjectivesWe aim to determine the expression and physiological function of Sigmar1 in skeletal muscle structure and function in mice.Methods and ResultsWe first confirmed the Sigmar1 mRNA and protein expression in different types of skeletal muscles (gastrocnemius, quadriceps, soleus, extensor digitorum longus (EDL), and tibialis anterior (TA)) isolated from mice. Immunostaining with the Sigmar1 antibody demonstrated Sigmar1’s localization predominantly in type 1 muscle. We used Sigmar1 global knockout (Sigmar1−/−) mice to determine the physiological function of Sigmar1 in skeletal muscle. Morphometric analysis showed normal muscle weight‐to‐tibia length ratio in all these muscles across the group. The cross‐sectional area of the muscles determined by WGA staining showed that quadriceps and gastrocnemius muscles isolated from Sigmar1−/− mice have bigger muscle fibers compared to wildtype (Wt) mice. Interestingly, absence of Sigmar1 in gastrocnemius and quadriceps muscle of Sigmar1−/− mice results in slow‐to‐fast fiber‐type switch. Interestingly, absence of Sigmar1 in different types of skeletal muscle isolated 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) compared to Wt mice.ConclusionsOur findings suggested an abundant expression of Sigmar1 in different types of skeletal muscle and possess an essential physiological function in these muscles. Sigmar1 absence results in alterations in muscle fiber size, increased number of central nuclei, fiber‐type switch, and fibrotic remodeling suggesting Sigmar1’s function in maintaining healthy skeletal muscle.Support or Funding InformationThis work was supported by NIH/NHLBI grants R00 HL122354, R01HL145753, R01HL145753‐01S1 and PGM121307A to Dr. Bhuiyan. American Heart Association postdoctoral fellowship to Dr. Alam; Malcolm Fiest post‐ and pre‐doctoral fellowships to Dr. Abdullah and Aishwarya by CCDS, LSUHSC‐S.