Fast skeletal myosin binding protein-C regulates fast skeletal muscle contraction
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA674604 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12979800_1.fastq.gz | Fastqsanger.gz | |||
| SRR12979800_2.fastq.gz | Fastqsanger.gz | |||
| SRR12979801_1.fastq.gz | Fastqsanger.gz | |||
| SRR12979801_2.fastq.gz | Fastqsanger.gz | |||
| SRR12979802_1.fastq.gz | Fastqsanger.gz |
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Project description:Fast skeletal myosin binding protein-C (fMyBP-C) is one of three MyBP-C paralogs and is predominantly expressed in fast skeletal muscle. Mutations in the gene that encodes fMyBP-C, MYBPC2, is associated with distal arthrogryposis, while fMyBP-C protein is reduced in diseased muscle. However, the functional and structural roles of fMyBP-C in skeletal muscle remain unclear. To address this gap, we generated a homozygous fMyBP-C knockout mouse (C2-/-) and characterized it, both in vivo and in vitro. Ablation of fMyBP-C was benign in terms of muscle weight, fiber type, cross-sectional area, and sarcomere ultrastructure. However, grip strength and plantar-flexor muscle strength were significantly decreased in C2-/- compared to WT. Peak isometric tetanic force (Po) and isotonic speed of contraction were significantly reduced in isolated extensor digitorum longus (EDL) from C2-/- mice. In EDL muscles of C2-/- mice, small-angle X-ray diffraction revealed significant increase in equatorial intensity ratio (I1.1/I1.0) during contraction, indicating a greater degree of myosin head shift towards actin while MLL4 layer-line intensity was decreased at rest, indicating less ordered myosin heads at rest. Interfilament lattice spacing was also significantly increased in C2-/- EDL muscle compared to WT. Consistent with these findings, we observed a significant reduction of steady-state isometric force during Ca2+ activations, myofilament calcium sensitivity, sinusoidal stiffness in skinned EDL muscle fibers from C2-/- mice. Finally, C2-/- muscles displayed disruption of inflammatory and regenerative genes and increased muscle damage upon mechanical overload. Together, our data suggest that fMyBP-C is essential for maximal speed and force of contraction, sarcomere integrity, and calcium sensitivity in fast twitch muscle.
2020-11-30 | GSE160827 | GEO
Project description:Myosin-binding protein C (MyBP-C) is a thick filament regulatory protein found exclusively in the C-zone of the A band in the sarcomeres of vertebrate striated muscle. Cardiac, slow skeletal and fast skeletal MyBP-C (fMyBP-C) paralogs perform different functions. However, the functional role of fMyBP-C in fast skeletal muscle is completely unknown. Genetic mutations in human fMyBP-C lead to skeletal myopathies. All three isoforms share similar protein structures, but likely differ substantially in terms of expression and function, which may serve the distinct physiologies of fast and slow muscle fibers. In the present study, we developed a novel fMyBP-C global knockout (KO) mouse model (C2-/-) to investigate the structural, functional, molecular, cellular and physiological roles of fMyBP-C in skeletal muscle.
2021-04-09 | PXD022316 | Pride
Project description:Fast skeletal myosin-binding protein-C (fMyBP-C) is one of three MyBP-C paralogs and is predominantly expressed in fast skeletal muscle. Mutations in the gene that encodes fMyBP-C, MYBPC2, are associated with distal arthrogryposis, while loss of fMyBP-C protein is associated with diseased muscle. However, the functional and structural roles of fMyBP-C in skeletal muscle remain unclear. To address this gap, we generated a homozygous fMyBP-C knockout mouse (C2-/-) and characterized it both in vivo and in vitro compared to wild-type mice. Ablation of fMyBP-C was benign in terms of muscle weight, fiber type, cross-sectional area, and sarcomere ultrastructure. However, grip strength and plantar flexor muscle strength were significantly decreased in C2-/- mice. Peak isometric tetanic force and isotonic speed of contraction were significantly reduced in isolated extensor digitorum longus (EDL) from C2-/- mice. Small-angle X-ray diffraction of C2-/- EDL muscle showed significantly increased equatorial intensity ratio during contraction, indicating a greater shift of myosin heads toward actin, while MLL4 layer line intensity was decreased at rest, indicating less ordered myosin heads. Interfilament lattice spacing increased significantly in C2-/- EDL muscle. Consistent with these findings, we observed a significant reduction of steady-state isometric force during Ca2+-activation, decreased myofilament calcium sensitivity, and sinusoidal stiffness in skinned EDL muscle fibers from C2-/- mice. Finally, C2-/- muscles displayed disruption of inflammatory and regenerative pathways, along with increased muscle damage upon mechanical overload. Together, our data suggest that fMyBP-C is essential for maximal speed and force of contraction, sarcomere integrity, and calcium sensitivity in fast-twitch muscle.
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Project description:Skeletal muscle is an inherently heterogenous tissue comprised primarily of myofibers, which are historically classified into three distinct fiber types in humans: one “slow” (type 1) and two “fast” (type 2A and type 2X), delineated by the expression of myosin heavy chain isoforms (MYHs). However, whether discrete fiber types exist or whether fiber heterogeneity reflects a continuum remains unclear. Furthermore, whether MYHs are the main classifiers of skeletal muscle fibers has not been examined in an unbiased manner. Through the development and application of novel transcriptomic and proteomic workflows, applied to 1050 and 1038 single muscle fibers from human vastus lateralis, respectively, we show that MYHs are not the principal drivers of skeletal muscle fiber heterogeneity. Instead, ribosomal heterogeneity drives the majority of variance between skeletal muscle fibers in a continual fashion, independent of slow/fast fiber type. Furthermore, whilst slow and fast fiber clusters can be identified, described by their contractile and metabolic profiles, our data challenge the concept that type 2X are phenotypically distinct from other fast fibers at an omics level. Moreover, MYH-based classifications do not adequately describe the phenotype of skeletal muscle fibers in one of the most common genetic muscle diseases, nemaline myopathy. Our data question the currently accepted model of multiple distinct fiber types based on the expression of MYHs in humans and identifies ribosomal heterogeneity as a major driver of skeletal muscle fiber heterogeneity, opening a new field of research within skeletal muscle physiology.
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Project description:Small mammals, such as mice, rely on the rapid contraction of skeletal muscles to achieve swift movements. These capabilities are enabled by type IIb myofibers, which express the fastest myosin IIb in limb muscles, encoded by MYH4. In contrast, larger mammals, including humans, exhibit a marked reduction or complete absence of type IIb myofibers and MYH4 expression, favoring slower-contracting myofiber types. The evolutionary shift away from MYH4 expression in larger mammals and the underlying regulatory mechanisms remain poorly understood. Previously, we identified the large Maf transcription factor family (Mafa, Mafb, Maf) as principal regulators of type IIb myofiber determination in mice. Here, we provide the first evidence that the large MAFs specifically induces MYH4 expression in the skeletal muscles of large mammals, including humans and bovine. Furthermore, induction of MYH4 by large MAFs significantly enhances the glycolytic capacity of human myotubes, as evidenced by flux analyzer data and RNA-seq showing the upregulation of numerous genes associated with glucose metabolism. Lastly, RNA-seq analysis of human muscle biopsies reveals a positive correlation between MAFA, MAF, and MYH4 expression. Our findings propose that the large MAFs promotes the formation of the fastest type IIb myofibers in the skeletal muscles of large mammals. This discovery not only elucidates the mechanisms underlying the loss of type IIb myofibers in larger mammals but also holds potential implications for enhancing athletic performance and counteracting the loss of fast-twitch myofibers associated with aging.
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