Cardiac myosin binding protein-C plays no regulatory role in skeletal muscle structure and function.

Sudhiranjan Gupta,Brian Lin,Roger Craig,K Elisabeth Runte,Suresh Govindan,Renzhi Han,Bradley M Palmer,Sakthivel Sadayappan,Piming Zhao,Kyounghwan Lee

doi:10.1371/journal.pone.0069671

Abstract

Myosin binding protein-C (MyBP-C) exists in three major isoforms: slow skeletal, fast skeletal, and cardiac. While cardiac MyBP-C (cMyBP-C) expression is restricted to the heart in the adult, it is transiently expressed in neonatal stages of some skeletal muscles. However, it is unclear whether this expression is necessary for the proper development and function of skeletal muscle. Our aim was to determine whether the absence of cMyBP-C alters the structure, function, or MyBP-C isoform expression in adult skeletal muscle using a cMyBP-C null mouse model (cMyBP-C(t/t)). Slow MyBP-C was expressed in both slow and fast skeletal muscles, whereas fast MyBP-C was mostly restricted to fast skeletal muscles. Expression of these isoforms was unaffected in skeletal muscle from cMyBP-C(t/t) mice. Slow and fast skeletal muscles in cMyBP-C(t/t) mice showed no histological or ultrastructural changes in comparison to the wild-type control. In addition, slow muscle twitch, tetanus tension, and susceptibility to injury were all similar to the wild-type controls. Interestingly, fMyBP-C expression was significantly increased in the cMyBP-C(t/t) hearts undergoing severe dilated cardiomyopathy, though this does not seem to prevent dysfunction. Additionally, expression of both slow and fast isoforms was increased in myopathic skeletal muscles. Our data demonstrate that i) MyBP-C isoforms are differentially regulated in both cardiac and skeletal muscles, ii) cMyBP-C is dispensable for the development of skeletal muscle with no functional or structural consequences in the adult myocyte, and iii) skeletal isoforms can transcomplement in the heart in the absence of cMyBP-C.

Highlights

Myosin binding protein-C (MyBP-C) is a modular thick filament protein belonging to the intracellular immunoglobulin (Ig) and fibronectin (Fn) superfamily (Figure 1)
To determine the differential expression of MyBP-C isoforms in adult muscle, extracts of cardiac and skeletal tissue from (t/t) and WT mice were probed by Western blotting for the slow, fast, and cardiac isoforms of MyBP-C, using antibodies known to be specific for these isoforms. cMyBP-C was not detected in either slow or fast skeletal muscle tissues (Figure 2A–C), confirming that cMyBP-C expression is restricted to the adult heart
We investigated the differential expression of MyBP-C isoforms in cardiac and skeletal muscles in mice lacking cMyBP-C and in dystrophic mice

Summary

Introduction

Myosin binding protein-C (MyBP-C) is a modular thick filament protein belonging to the intracellular immunoglobulin (Ig) and fibronectin (Fn) superfamily (Figure 1). It is found in vertebrate cardiac and skeletal muscle and has both regulatory and structural functions [1,2]. There are 3 isoforms of MyBP-C, each encoded by a distinct gene: fast-skeletal, slow-skeletal, and cardiac [10,11,12,13]. The two skeletal isoforms of MyBP-C expressed in mature skeletal muscles are slow MyBP-C (sMyBP-C) and fast MyBP-C (fMyBP-C), encoded by the MYBPC1 and MYBPC2 genes, respectively (Table 1). MYBPC1 mutations cause distal arthrogryposis type 1 [17], while mutations in MYBPC3 are associated with the development of hypertrophic cardiomyopathy (HCM) [18,19]

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