Molecular Characterization of Skeletal Muscle Dysfunction in Sigma 1 Receptor (Sigmar1) Knockout Mice.

Abstract

Sigma 1 receptor (Sigmar1) is a widely expressed, multitasking molecular chaperone protein that plays functional roles in several cellular processes. Mutations in the Sigmar1 gene are associated with several distal neuropathies with strong manifestation in skeletal muscle dysfunction with phenotypes like muscle wasting and atrophy. However, the physiological function of Sigmar1 in skeletal muscle remains unknown. Herein, the physiological role of Sigmar1 in skeletal muscle structure and function in gastrocnemius, quadriceps, soleus, extensor digitorum longus, and tibialis anterior muscles was determined. Quantification of myofiber cross-sectional area showed altered myofiber size distribution and changes in myofiber type in the skeletal muscle of the Sigmar1-/- mice. Interestingly, ultrastructural analysis by transmission electron microscopy showed the presence of abnormal mitochondria, and immunostaining showed derangements in dystrophin localization in skeletal muscles from Sigmar1-/- mice. In addition, 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 without any changes in voluntary locomotion, markers for muscle denervation, and muscle atrophy. Overall, this study shows, for the first time, a potential physiological function of Sigmar1 in maintaining healthy skeletal muscle structure and function.

• Authors: Richa Aishwarya, Chowdhury S Abdullah, Naznin S Remex, Shafiul Alam, Mahboob Morshed, Sadia Nitu, Brandon Hartman, Judy King, Mohammad Alfrad Nobel Bhuiyan, A Wayne Orr, Christopher G Kevil, Md Shenuarin Bhuiyan
• Journal: The American journal of pathology (Am J Pathol) Vol. 192 Issue 1 Pg. 160-177 (01 2022) ISSN: 1525-2191 [Electronic] United States
• PMID: 34710383 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Dystrophin
• Receptors, sigma
• Collagen

Topics

• Animals
• Collagen (metabolism)
• Dystrophin (metabolism)
• Fibrosis
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria (metabolism, ultrastructure)
• Muscle Fibers, Skeletal (pathology)
• Muscle, Skeletal (metabolism, physiopathology, ultrastructure)
• Physical Conditioning, Animal
• Protein Transport
• Receptors, sigma (deficiency, metabolism)
• Sigma-1 Receptor
• Mice