Type IIx myosin heavy chain transcripts are expressed in type IIB fibers of human skeletal muscle
Several members of the sarcomeric myosin heavy chain (MHC) gene family have been mapped in the human genome but many of them have not yet been identified. In this study we report the identification of two human skeletal MHC genes as fast IIa and IIx MHC based on pattern of expression and sequence homology with the corresponding rat genes in the 3'-translated and untranslated regions. The distribution of these two gene products as well as that of the beta/slow MHC gene was analyzed in human skeletal muscles by in situ hybridization. The distribution of beta/slow, IIa, and IIx MHC transcripts defines three major muscle fiber types expressing a single MHC mRNA, i.e., either beta/slow, IIa, or IIx MHC mRNA, and two populations of hybrid fibers coexpressing beta/slow with IIa or IIa with IIx MHC mRNA. Fiber typing by ATPase histochemistry shows that IIa MHC transcripts are more abundant in histochemical type IIa fibers, whereas IIx MHC transcripts are more abundant in histochemical type IIb fibers.
Available from: Michela Catteruccia
- "Three major isoforms are known in adult human limb muscle fibers: MyHC I, encoded by MYH7 and expressed in slow type I muscle fibers and in heart ventricles; MyHC IIa, encoded by MYH2 and expressed in fast type IIA muscle fibers, and MyHC IIx expressed in fast type IIB muscle fibers . To date pathogenetic mutations associated to hereditary myopathies have been identified in both MYH7 and MYH2 genes . The first pathogenetic MYH2 mutation, reported by Martinsson and coauthors in 2000 , was a dominant missense mutation in exon 17 (c.2116, "
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ABSTRACT: Congenital myopathy related to mutations in myosin MyHC IIa gene (MYH2) is a rare neuromuscular disease. A single dominant missense mutation has been reported so far in a family in which the affected members had congenital joint contractures at birth, external ophthalmoplegia and proximal muscle weakness. Afterward only additional 4 recessive mutations have been identified in 5 patients presenting a mild non-progressive early-onset myopathy associated with ophthalmoparesis. We report a new de novo MYH2 missense mutation in a baby affected by a congenital myopathy characterized by severe dysphagia, respiratory distress at birth and external ophthalmoplegia. We describe clinical, histopathological and muscle imaging findings expanding the clinical and genetic spectrum of MYH2-related myopathy.
Available from: link.springer.com
- "There are several striated muscle MyHC isoforms encoded by different genes and expressed in a tissue and developmental specific manner [61–63, 84, 85]. In adult human limb skeletal muscle there are three major MyHC isoforms: MyHC I, also called slow/ß-cardiac MyHC, is encoded by MYH7 and is expressed in slow, type 1 muscle fibers as well as in the ventricles of the heart; MyHC IIa (MYH2) is expressed in fast, type 2A muscle fibers and MyHC IIx (MYH1) is expressed in fast, type 2B muscle fibers  (Table 1). The three different muscle fiber types differ in their contractile and physiological properties, which are partly determined by the different MyHCs. "
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ABSTRACT: The myosin heavy chain (MyHC) is the molecular motor of muscle and forms the backbone of the sarcomere thick filaments. Different MyHC isoforms are of importance for the physiological properties of different muscle fiber types. Hereditary myosin myopathies have emerged as an important group of diseases with variable clinical and morphological expression depending on the mutated isoform and type and location of the mutation. Dominant mutations in developmental MyHC isoform genes (MYH3 and MYH8) are associated with distal arthrogryposis syndromes. Dominant or recessive mutations affecting the type IIa MyHC (MYH2) are associated with early-onset myopathies with variable muscle weakness and ophthalmoplegia as a consistent finding. Myopathies with scapuloperoneal, distal or limb-girdle muscle weakness including entities, such as myosin storage myopathy and Laing distal myopathy are the result of usually dominant mutations in the gene for slow/β cardiac MyHC (MYH7). Protein aggregation is part of the features in some of these myopathies. In myosin storage myopathy protein aggregates are formed by accumulation of myosin beneath the sarcolemma and between myofibrils. In vitro studies on the effects of different mutations associated with myosin storage myopathy and Laing distal myopathy indicate altered biochemical and biophysical properties of the light meromyosin, which is essential for thick filament assembly. Protein aggregates in the form of tubulofilamentous inclusions in association with vacuolated muscle fibers are present at late stage of dominant myosin IIa myopathy and sometimes in Laing distal myopathy. These protein aggregates exhibit features indicating defective degradation of misfolded proteins. In addition to protein aggregation and muscle fiber degeneration some of the myosin mutations cause functional impairment of the molecular motor adding to the pathogenesis of myosinopathies.
Available from: Andrew J Galpin
- "Human muscle fiber types can be defined in various ways with the contractile protein myosin heavy chain (MHC), 1 a common identifier. MHC is found in the forms of types I, IIa, and IIx, and muscle fibers can contain only one (i.e., a pure fiber ) or a combination (i.e., a hybrid fiber) of these isoforms, giving rise to the five most prevalent muscle fiber types in humans (I, I/ IIa, IIa, IIa/IIx, and IIx)[3,4]. Once thought to be mostly static in adult humans[5,6], the fiber type profile of human skeletal muscle has now been shown to have a high degree of plasticity, with a primary regulator of fiber type alterations being physical activity789101112131415. A major focus of our laboratory for the past 15 years has been to examine alterations in human single muscle fiber size, MHC composition , and contractile function with changes in physical activity patterns. "
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ABSTRACT: The aim of this project was to develop a method to assess fiber type specific protein content across the continuum of human skeletal muscle fibers. Individual vastus lateralis muscle fibers (n = 264) were clipped into two portions: one for sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) fiber typing and one for Western blot protein identification. Following fiber type determination, fiber segments were combined into fiber type specific pools (∼20 fibers/pool) and measured for total protein quantity, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), citrate synthase (CS), and total p38 content. GAPDH content was 64, 54, 160, and 138% more abundant in myosin heavy chain (MHC) I/IIa, MHC IIa, MHC IIa/IIx, and MHC IIx fibers, respectively, when compared with MHC I. Inversely, CS content was 528, 472, 242, and 47% more abundant in MHC I, MHC I/IIa, MHC IIa, and MHC IIa/IIx fibers, respectively, when compared with MHC IIx. Total p38 content was 87% greater in MHC IIa versus MHC I fibers. These data and this approach establish a reliable method for human skeletal muscle fiber type specific protein analysis. Initial results show that particular proteins exist in a hierarchal fashion throughout the continuum of human skeletal muscle fiber types, further highlighting the necessity of fiber type specific analysis.
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