Etiology of genetic muscle disorders induced by mutations in fast and slow skeletal MyBP-C paralogs

Abstract

Skeletal muscle, a highly complex muscle type in the eukaryotic system, is characterized by different muscle subtypes and functions associated with specific myosin isoforms. As a result, skeletal muscle is the target of numerous diseases, including distal arthrogryposes (DAs). Clinically, DAs are a distinct disorder characterized by variation in the presence of contractures in two or more distal limb joints without neurological issues. DAs are inherited, and up to 40% of patients with this condition have mutations in genes that encode sarcomeric protein, including myosin heavy chains, troponins, and tropomyosin, as well as myosin binding protein-C (MYBPC). Our research group and others are actively studying the specific role of MYBPC in skeletal muscles. The MYBPC family of proteins plays a critical role in the contraction of striated muscles. More specifically, three paralogs of the MYBPC gene exist, and these are named after their predominant expression in slow-skeletal, fast-skeletal, and cardiac muscle as sMyBP-C, fMyBP-C, and cMyBP-C, respectively, and encoded by the MYBPC1, MYBPC2, and MYBPC3 genes, respectively. Although the physiology of various types of skeletal muscle diseases is well defined, the molecular mechanism underlying the pathological regulation of DAs remains to be elucidated. In this review article, we aim to highlight recent discoveries involving the role of skeletal muscle-specific sMyBP-C and fMyBP-C as well as their expression profile, localization in the sarcomere, and potential role(s) in regulating muscle contractility. Thus, this review provides an overall summary of MYBPC skeletal paralogs, their potential roles in skeletal muscle function, and future research directions.

Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure

“…2D; Table 2), suggesting that fMyBP-C impacts lattice order across SLs potentially via thin filament interactions 21,28 . sMyBP-C and fMyBP-C have well-characterized structural differences in their N-termini, yet differences in functionality are still not fully described 19,30 . With only sMyBP-C in the C2 -/- fibers and a mix of MyBP-C isoforms in the NTG, our results for d 1,0 and σ D suggest that sMyBP-C supports or allows a greater radial distance between myofilaments compared to fMyBP-C.…”

“…1A) with the C'-terminus bound to the thick filament (C8-C10), and the other N'-terminal domains (C1-C7) pointed away from the thick filament, most likely interacting with myosin heads and the thin filament 22,23,28,29 . Skeletal muscles contain fast (fMyBP-C) and slow (sMpBP-C) isoforms that may function differently and are not necessarily fiber-type specific 19 . It was recently shown that rapid removal of the C1-C7 domains of fMyBP-C in the fast-twitch dominant psoas muscle led to an SL-independent movement of myosin heads towards the ON state, but the SL-dependent transition of myosin heads towards the ON state at longer vs. shorter SLs was largely intact 18 .…”

Myosin-binding protein C forms C-links and stabilizes OFF states of myosin

“…Mutations in the skeletal muscle paralogs lead to debilitating myopathies in humans including severe and lethal forms of distal arthrogryposis myopathy 10,11 and lethal congenital contracture syndrome 9 , suggesting a critical role in healthy sarcomere function. In addition, fMyBP-C knockout mice present altered force generation with myosin heads (i.e., free-heads) shifted towards the ON state 9,26 , suggesting that MyBP-C helps stabilize the myosin OFF state and/or suppresses OFF-to-ON transitions 26–28 . Importantly, MyBP-C effects can be blunted via post-translational modifications such as phosphorylation 29–31 , which can be altered in some myopathies but also in healthy muscle during exercise, e.g., via increased PKA/PKC activity 32 .…”

Bringing into focus the central domains C3-C6 of myosin binding protein C

“…Myosin binding protein C (MyBPC) is an essential regulator of contractile function in skeletal and cardiac muscle ( Bennett et al, 1999 ; Oakley et al, 2004 ; Heling et al, 2020 ; Song et al, 2023 ). Initially, MyBPC was visualized as an unknown thick filament structure in frog sartorius muscle via low-angle X-ray diffraction experiments and stripes of extra mass 43 nm apart in long sections of muscle ( Huxley, 1967 ; Huxley and Brown, 1967 ).…”