Title

Fast skeletal myosin-binding protein-C regulates fast skeletal muscle contraction

UMMS Affiliation

Division of Cell Biology and Imaging, Department of Radiology; Craig Lab

Publication Date

2021-04-27

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cellular and Molecular Physiology | Musculoskeletal Diseases | Musculoskeletal System

Abstract

Fast skeletal myosin-binding protein-C (fMyBP-C) is one of three MyBP-C paralogs and is predominantly expressed in fast skeletal muscle. Mutations in the gene that encodes fMyBP-C, MYBPC2, are associated with distal arthrogryposis, while loss of fMyBP-C protein is associated with diseased muscle. However, the functional and structural roles of fMyBP-C in skeletal muscle remain unclear. To address this gap, we generated a homozygous fMyBP-C knockout mouse (C2(-/-)) and characterized it both in vivo and in vitro compared to wild-type mice. Ablation of fMyBP-C was benign in terms of muscle weight, fiber type, cross-sectional area, and sarcomere ultrastructure. However, grip strength and plantar flexor muscle strength were significantly decreased in C2(-/-) mice. Peak isometric tetanic force and isotonic speed of contraction were significantly reduced in isolated extensor digitorum longus (EDL) from C2(-/-) mice. Small-angle X-ray diffraction of C2(-/-) EDL muscle showed significantly increased equatorial intensity ratio during contraction, indicating a greater shift of myosin heads toward actin, while MLL4 layer line intensity was decreased at rest, indicating less ordered myosin heads. Interfilament lattice spacing increased significantly in C2(-/-) EDL muscle. Consistent with these findings, we observed a significant reduction of steady-state isometric force during Ca(2+-)activation, decreased myofilament calcium sensitivity, and sinusoidal stiffness in skinned EDL muscle fibers from C2(-/-) mice. Finally, C2(-/-) muscles displayed disruption of inflammatory and regenerative pathways, along with increased muscle damage upon mechanical overload. Together, our data suggest that fMyBP-C is essential for maximal speed and force of contraction, sarcomere integrity, and calcium sensitivity in fast-twitch muscle.

Keywords

MYBPC2, contraction, distal arthrogryposis, fMyBP-C, skeletal muscle

DOI of Published Version

10.1073/pnas.2003596118

Source

Song T, McNamara JW, Ma W, Landim-Vieira M, Lee KH, Martin LA, Heiny JA, Lorenz JN, Craig R, Pinto JR, Irving T, Sadayappan S. Fast skeletal myosin-binding protein-C regulates fast skeletal muscle contraction. Proc Natl Acad Sci U S A. 2021 Apr 27;118(17):e2003596118. doi: 10.1073/pnas.2003596118. PMID: 33888578; PMCID: PMC8092462. Link to article on publisher's site

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Related Resources

Link to Article in PubMed

PubMed ID

33888578

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