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

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 Ca2+-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.

• Authors: Taejeong Song, James W McNamara, Weikang Ma, Maicon Landim-Vieira, Kyoung Hwan Lee, Lisa A Martin, Judith A Heiny, John N Lorenz, Roger Craig, Jose Renato Pinto, Thomas Irving, Sakthivel Sadayappan
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 17 (04 27 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 33888578 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Actins
• Carrier Proteins
• myosin-binding protein C
• Myosins
• Calcium

Topics

• Actin Cytoskeleton (metabolism)
• Actins (metabolism)
• Animals
• Calcium (metabolism)
• Carrier Proteins (metabolism)
• Isometric Contraction (physiology)
• Mice
• Muscle Contraction (physiology)
• Muscle Fibers, Fast-Twitch (metabolism)
• Muscle Strength
• Muscle, Skeletal (metabolism)
• Myofibrils (metabolism)
• Myosins (metabolism)
• Sarcomeres (metabolism)