Scientists at the University of Cincinnati and colleagues report that a regulatory protein found in skeletal muscle fiber may play an important role in the body’s fight or flight response when encountering stressful situations.

The protein, fast skeletal myosin binding protein-C (fMyBP-C), plays a foundational role in the proper regulation of contractile structure and function in the body’s fast-twitch muscles, which produce sudden bursts of power to sprint into action, jump or lift heavy objects. Fast skeletal myosin binding protein-C modulates the speed and force of fast skeletal muscle contraction.

The researchers, who published their study (“Fast skeletal myosin-binding protein-C regulates fast skeletal muscle contraction”) in PNAS, say advancing the knowledge of fast myosin binding protein-C may someday assist in addressing skeletal muscular disorders.

“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,” write the investigators.

“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.”

“This response is very critical for the higher animal and human survival. Just imagine, you are walking through a forest and suddenly you see a tiger in front of you,” says Sakthivel Sadayappan, PhD, a professor in the UC Division of Cardiovascular Health and Disease. “You will immediately act, either to fight or run away from the animal. For that action, fast muscle is essential, and fast myosin binding protein-C is the key molecule to regulate the speed of action.”

Myosin-binding protein-C is a thick filament regulatory protein found in striated muscle in both the heart and skeletal system. The protein performs different functions in the two organs, regulating contractility in the heart and playing a role in the development of fast and slow muscle fibers in skeletal muscle tissue.

Sadayappan, along with researchers at UC College of Medicine, Florida State University, the University of Massachusetts Medical School and the Illinois Institute of Technology published their work to further the understanding of the protein in skeletal function and regulation.

The study’s lead author is Taejeong Song, PhD, a postdoctoral fellow in the Sadayappan Lab at the UC College of Medicine. Song says that research examined the role of the protein in fast-twitch muscles by generating a knockout mouse whose fast myosin binding protein-C gene had been either inactivated, replaced, or disrupted.

“We found that knockout mice demonstrated a reduced ability to exercise, showed less maximal muscle force and a diminished ability for muscle to recover from injury,” explains Sadayappan. “Our study concludes that fast myosin binding protein-C is essential in regulating the force generation and speed of contraction of fast muscles.

“Individuals lose their ability of muscle force generation for various reasons. They may be extremely inactive or hospitalized for long periods of time. Aging may also be the cause for some. We also think if we can manipulate the workings of fast myosin binding protein-C in skeletal muscle that we can prevent or at least slow down the loss of muscle function in genetic muscle disease such as distal arthrogryposis. Our research is trying to figure out this problem in human health.”

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