Abstract
Myosin binding protein-C (MyBP-C), a major thick filament associated sarcomeric protein, plays an important functional and structural role in regulating sarcomere assembly and crossbridge formation. Missing or aberrant MyBP-C proteins (both cardiac and skeletal) have been shown to cause both cardiac and skeletal myopathies, thereby emphasising its importance for the normal functioning of the sarcomere. Mutations in cardiac MyBP-C are a major cause of hypertrophic cardiomyopathy (HCM), while mutations in skeletal MyBP-C have been implicated in a disease of skeletal muscle—distal arthrogryposis type 1 (DA-1). Here we report the first detailed electron microscopy studies on human cardiac and skeletal tissues carrying MyBP-C gene mutations, using samples obtained from HCM and DA-1 patients. We have used established image averaging methods to identify and study the axial distribution of MyBP-C on the thick filament by averaging profile plots of the A-band of the sarcomere from electron micrographs of human cardiac and skeletal myopathy specimens. Due to the difficulty of obtaining normal human tissue, we compared the distribution to the A-band structure in normal frog skeletal, rat cardiac muscle and in cardiac muscle of MyBP-C-deficient mice. Very similar overall profile averages were obtained from the C-zones in cardiac HCM samples and skeletal DA-1 samples with MyBP-C gene mutations, suggesting that mutations in MyBP-C do not alter its mean axial distribution along the thick filament.
Highlights
Myosin binding protein-C (MyBP-C) is a 140 kDa sarcomeric protein that binds to the thick filament in vertebrate striated muscle and can be visualised as 7–9 stripes of separation 43 nm in the C-zone of the sarcomere
Mutations in cardiac MyBP-C are a major cause of hypertrophic cardiomyopathy (HCM), while mutations in skeletal MyBP-C have been implicated in a disease of skeletal muscle—distal arthrogryposis type 1 (DA-1)
Human cardiac samples used in this study were obtained from inter-ventricular septum of HCM patients undergoing surgical myectomy to relieve hypertrophic obstructive cardiomyopathy
Summary
Myosin binding protein-C (MyBP-C) is a 140 kDa sarcomeric protein that binds to the thick filament in vertebrate striated muscle and can be visualised as 7–9 stripes of separation 43 nm in the C-zone of the sarcomere. J Muscle Res Cell Motil (2012) 33:61–74 discovered in skeletal muscle nearly 40 years ago by Offer et al (1973) as a contaminant in the preparation of purified myosin. All three isoforms share a conserved domain architecture, composed of seven immunoglobulin (IgI) domains and three fibronectin type III (FnIII) domains depicted as C1–C10 (Fig. 1a), with a 105 residue domain between C1 and C2 called the M-domain or MyBP-C motif and a proline- and alaninerich region near the N-terminus (Gautel et al 1995; Okagaki et al 1993). The cardiac isoform differs from the skeletal isoform in three major ways: it has an additional Ig domain, C0, at the N-terminus; it has 3 phosphorylation sites in the M-domain and the domain C5 has a proline-rich 25 residue insertion (Gautel et al 1995). The homology of the amino acids in all three isoforms is high, with 39.6 % sequence identity in the human isoforms
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