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Axial distribution of myosin binding protein-C is unaffected by mutations in human cardiac and skeletal muscle.

Vydyanath A, Gurnett CA, Marston S, Luther PK - J. Muscle Res. Cell. Motil. (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK. a.vydyanath@imperial.ac.uk

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.

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Transmission electron micrographs of the skeletal biopsy samples. Low and medium magnification overview of myofibrillar and sarcomeric ultrastructure of a–c ss-W236R and d–f ss-Y856H. a, d show micrographs of regions with well-aligned and straight myofibrils; b, e EM of myofibrils showing a “bent” appearance; c, f EM micrographs of sarcomeres with good visual structure showing well-defined M-bands and Z-discs. Bar = 1 μm
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Fig3: Transmission electron micrographs of the skeletal biopsy samples. Low and medium magnification overview of myofibrillar and sarcomeric ultrastructure of a–c ss-W236R and d–f ss-Y856H. a, d show micrographs of regions with well-aligned and straight myofibrils; b, e EM of myofibrils showing a “bent” appearance; c, f EM micrographs of sarcomeres with good visual structure showing well-defined M-bands and Z-discs. Bar = 1 μm

Mentions: The effects of the MyBP-C gene mutations on the general features and ultrastructural organisation of the diseased skeletal and cardiac muscle was studied by electron microscopy at a range of low-medium magnifications (Figs. 3, 4). Longitudinal sections of the muscle were examined for signs of myofibrillar disarray and disorder within sarcomeres. The electron micrographs of the skeletal mutations (ss-W236R and ss-Y856H) exhibited regions with well-aligned and straight myofibrils (Fig. 3a, d), as well as, myofibrils with a bent appearance (Fig. 3b, e). However, the sarcomere itself is well preserved, and features such as the Z-disc, M-band and I-bands are clearly visible.Fig. 3


Axial distribution of myosin binding protein-C is unaffected by mutations in human cardiac and skeletal muscle.

Vydyanath A, Gurnett CA, Marston S, Luther PK - J. Muscle Res. Cell. Motil. (2012)

Transmission electron micrographs of the skeletal biopsy samples. Low and medium magnification overview of myofibrillar and sarcomeric ultrastructure of a–c ss-W236R and d–f ss-Y856H. a, d show micrographs of regions with well-aligned and straight myofibrils; b, e EM of myofibrils showing a “bent” appearance; c, f EM micrographs of sarcomeres with good visual structure showing well-defined M-bands and Z-discs. Bar = 1 μm
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351610&req=5

Fig3: Transmission electron micrographs of the skeletal biopsy samples. Low and medium magnification overview of myofibrillar and sarcomeric ultrastructure of a–c ss-W236R and d–f ss-Y856H. a, d show micrographs of regions with well-aligned and straight myofibrils; b, e EM of myofibrils showing a “bent” appearance; c, f EM micrographs of sarcomeres with good visual structure showing well-defined M-bands and Z-discs. Bar = 1 μm
Mentions: The effects of the MyBP-C gene mutations on the general features and ultrastructural organisation of the diseased skeletal and cardiac muscle was studied by electron microscopy at a range of low-medium magnifications (Figs. 3, 4). Longitudinal sections of the muscle were examined for signs of myofibrillar disarray and disorder within sarcomeres. The electron micrographs of the skeletal mutations (ss-W236R and ss-Y856H) exhibited regions with well-aligned and straight myofibrils (Fig. 3a, d), as well as, myofibrils with a bent appearance (Fig. 3b, e). However, the sarcomere itself is well preserved, and features such as the Z-disc, M-band and I-bands are clearly visible.Fig. 3

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK. a.vydyanath@imperial.ac.uk

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.

Show MeSH
Related in: MedlinePlus