Abstract
Myosin Binding Protein-C slow (sMyBP-C), encoded by MYBPC1, comprises a family of regulatory proteins of skeletal muscles that are phosphorylated by PKA and PKC. MYBPC1 missense mutations are linked to the development of Distal Arthrogryposis-1 (DA-1). Although structure-function details for this myopathy are evolving, function is undoubtedly driven by sequence variations and post-translational modifications in sMyBP-C. Herein, we examined the phosphorylation profile of sMyBP-C in mouse and human fast-twitch skeletal muscles. We used Flexor Digitorum Brevis (FDB) isolated from young (~2-months old) and old (~14-months old) wild type and mdx mice, and human Abductor Hallucis (AH) and gastrocnemious muscles carrying the DA-1 mutations. Our results indicate both constitutive and differential phosphorylation of sMyBP-C in aged and diseased muscles. We report a 7–35% reduction in the phosphorylation levels of select sites in old wild type and young or old mdx FDB mouse muscles, compared to young wild type tissue. Similarly, we observe a 30–70% decrease in the phosphorylation levels of all PKA and PKC phospho-sites in the DA-1 AH, but not gastrocnemius, muscle. Overall, our studies show that the phosphorylation pattern of sMyBP-C is differentially regulated in response to age and disease, suggesting that phosphorylation plays important roles in these processes.
Highlights
Myosin Binding Protein-C (MyBP-C) is a family of accessory proteins of striated muscles that contributes to thick filament assembly and stabilization, and modulates contraction by regulating the formation of actomyosin cross-bridges[1,2,3,4,5,6,7,8]
We compared the phosphorylation profile of sMyBP-C in young (~2 months old) and old (~14 months old) fast-twitch Flexor Digitorum Brevis (FDB) muscles obtained from wild type and mdx mice, and human Abductor Hallucis (AH) and gastrocnemius fast-twitch muscles carrying the Y856H and W236R mutations, respectively
Our recent studies have demonstrated that sMyBP-C encompasses a family of phosphoproteins with mSer-59 and mSer-62 phosphorylated by PKA, mThr-84 phosphorylated by PKC, and mSer-204 phosphorylated by both PKA and PKC11
Summary
Myosin Binding Protein-C (MyBP-C) is a family of accessory proteins of striated muscles that contributes to thick filament assembly and stabilization, and modulates contraction by regulating the formation of actomyosin cross-bridges[1,2,3,4,5,6,7,8]. The human transcriptome contains fourteen sMyBP-C transcripts, which encode fourteen distinct variants, differing by small segments of amino acids within the Pro/Ala rich motif, the M-motif, the Ig domain C7, and the extreme COOH-terminus[10]. MyBP-C slow is phosphorylated at four residues within the Pro/Ala rich region and the M-motif at its NH2-terminus[11]. These four sites (mSer-59/hSer-61, mSer-62/hThr-64, mThr-84/hSer-85, and mSer204/hSer-206) are conserved between mouse (m) and human (h) sMyBP-C and are phosphorylated by PKA and/or PKC11. Of the four phosphorylation sites, mSer-62/hThr-64 and mThr-84/hSer-85 are constitutively expressed in all known mouse and human variants (Fig. 1, grey highlighted residues). Our studies are the first to demonstrate that the phosphorylation pattern of sMyBP-C is differentially regulated in response to age and disease
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