Sorting of a nonmuscle tropomyosin to a novel cytoskeletal compartment in skeletal muscle results in muscular dystrophy

Tropomyosin (Tm) is a key component of the actin cytoskeleton and >40 isoforms have been described in mammals. In addition to the isoforms in the sarcomere, we now report the existence of two nonsarcomeric (NS) isoforms in skeletal muscle. These isoforms are excluded from the thin filament of the sarcomere and are localized to a novel Z-line adjacent structure. Immunostained cross sections indicate that one Tm defines a Z-line adjacent structure common to all myofibers, whereas the second Tm defines a spatially distinct structure unique to muscles that undergo chronic or repetitive contractions. When a Tm (Tm3) that is normally absent from muscle was expressed in mice it became associated with the Z-line adjacent structure. These mice display a muscular dystrophy and ragged-red fiber phenotype, suggestive of disruption of the membrane-associated cytoskeletal network. Our findings raise the possibility that mutations in these tropomyosin and these structures may underpin these types of myopathies.

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Faculty Opinions recommendation of microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717397850.793153110 ◽

2012 ◽

Author(s):

Michael Rudnicki ◽

Alessandra Pasut

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Regeneration ◽

Skeletal Muscle Regeneration

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Annexins and Membrane Repair Dysfunctions in Muscular Dystrophies

International Journal of Molecular Sciences ◽

10.3390/ijms22105276 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5276

Author(s):

Coralie Croissant ◽

Romain Carmeille ◽

Charlotte Brévart ◽

Anthony Bouter

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Genetic Disorders ◽

Muscle Cells ◽

Cell Types ◽

Clinical Severity ◽

Skeletal Muscle Cells ◽

Muscular Dystrophies ◽

Membrane Repair ◽

Human Skeletal Muscle Cells

Muscular dystrophies constitute a group of genetic disorders that cause weakness and progressive loss of skeletal muscle mass. Among them, Miyoshi muscular dystrophy 1 (MMD1), limb girdle muscular dystrophy type R2 (LGMDR2/2B), and LGMDR12 (2L) are characterized by mutation in gene encoding key membrane-repair protein, which leads to severe dysfunctions in sarcolemma repair. Cell membrane disruption is a physiological event induced by mechanical stress, such as muscle contraction and stretching. Like many eukaryotic cells, muscle fibers possess a protein machinery ensuring fast resealing of damaged plasma membrane. Members of the annexins A (ANXA) family belong to this protein machinery. ANXA are small soluble proteins, twelve in number in humans, which share the property of binding to membranes exposing negatively-charged phospholipids in the presence of calcium (Ca2+). Many ANXA have been reported to participate in membrane repair of varied cell types and species, including human skeletal muscle cells in which they may play a collective role in protection and repair of the sarcolemma. Here, we discuss the participation of ANXA in membrane repair of healthy skeletal muscle cells and how dysregulation of ANXA expression may impact the clinical severity of muscular dystrophies.

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Enzyme studies of skeletal muscle in mice with hereditary muscular dystrophy

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1963.205.5.897 ◽

1963 ◽

Vol 205 (5) ◽

pp. 897-901 ◽

Cited By ~ 45

Author(s):

Marilyn W. McCaman

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Glutathione Reductase ◽

Enzyme Activities ◽

Lactic Dehydrogenase ◽

Normal Muscle ◽

Dystrophic Muscle ◽

Nerve Section ◽

Mouse Muscle ◽

Dystrophic Mouse

The activities of 20 enzymes in normal, heterozygous, and dystrophic mouse muscle were studied by means of quantitative microchemical methods. Enzyme activities in normal and heterozygous muscle were essentially the same. In dystrophic muscle glucose-6-P dehydrogenase, 6-P-gluconic dehydrogenase, glutathione reductase, peptidase, ß-glucuronidase, and glucokinase activities were significantly higher than in normal muscle, while α-glycero-P dehydrogenase and lactic dehydrogenase activities were significantly lower. The pattern of enzyme activities found in normal gastrocnemius denervated by nerve section was strikingly similar to that in dystrophic muscle.

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Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

JRSM Cardiovascular Disease ◽

10.1177/2048004019879581 ◽

2019 ◽

Vol 8 ◽

pp. 204800401987958

Author(s):

HR Spaulding ◽

C Ballmann ◽

JC Quindry ◽

MB Hudson ◽

JT Selsby

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Gene Mutations ◽

Dystrophin Gene ◽

Mdx Mice ◽

Dystrophin Deficiency ◽

Muscle Wasting Disease ◽

Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

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The KATP channel Kir6.2 subunit content is higher in glycolytic than oxidative skeletal muscle fibers

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00663.2010 ◽

2011 ◽

Vol 301 (4) ◽

pp. R916-R925 ◽

Cited By ~ 18

Author(s):

Krystyna Banas ◽

Charlene Clow ◽

Bernard J. Jasmin ◽

Jean-Marc Renaud

Keyword(s):

Skeletal Muscle ◽

Cross Sections ◽

Fiber Type ◽

Energy Levels ◽

Muscle Fibers ◽

Metabolic Stress ◽

Oxidative Capacity ◽

Fiber Types ◽

Fiber Damage ◽

The Individual

It has long been suggested that in skeletal muscle, the ATP-sensitive K+ channel (KATP) channel is important in protecting energy levels and that abolishing its activity causes fiber damage and severely impairs function. The responses to a lack of KATP channel activity vary between muscles and fibers, with the severity of the impairment being the highest in the most glycolytic muscle fibers. Furthermore, glycolytic muscle fibers are also expected to face metabolic stress more often than oxidative ones. The objective of this study was to determine whether the t-tubular KATP channel content differs between muscles and fiber types. KATP channel content was estimated using a semiquantitative immunofluorescence approach by staining cross sections from soleus, extensor digitorum longus (EDL), and flexor digitorum brevis (FDB) muscles with anti-Kir6.2 antibody. Fiber types were determined using serial cross sections stained with specific antimyosin I, IIA, IIB, and IIX antibodies. Changes in Kir6.2 content were compared with changes in CaV1.1 content, as this Ca2+ channel is responsible for triggering Ca2+ release from sarcoplasmic reticulum. The Kir6.2 content was the lowest in the oxidative soleus and the highest in the glycolytic EDL and FDB. At the individual fiber level, the Kir6.2 content within a muscle was in the order of type IIB > IIX > IIA ≥ I. Interestingly, the Kir6.2 content for a given fiber type was significantly different between soleus, EDL, and FDB, and highest in FDB. Correlations of relative fluorescence intensities from the Kir6.2 and CaV1.1 antibodies were significant for all three muscles. However, the variability in content between the three muscles or individual fibers was much greater for Kir6.2 than for CaV1.1. It is suggested that the t-tubular KATP channel content increases as the glycolytic capacity increases and as the oxidative capacity decreases and that the expression of KATP channels may be linked to how often muscles/fibers face metabolic stress.

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Physiology of a Microgravity Environment Invited Review: Microgravity and skeletal muscle

Journal of Applied Physiology ◽

10.1152/jappl.2000.89.2.823 ◽

2000 ◽

Vol 89 (2) ◽

pp. 823-839 ◽

Cited By ~ 332

Author(s):

Robert H. Fitts ◽

Danny R. Riley ◽

Jeffrey J. Widrick

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Thin Filament ◽

Molecular Mechanisms ◽

Skeletal Muscle Atrophy ◽

Microgravity Environment ◽

Type I ◽

Fiber Types ◽

Maximal Velocity ◽

Cross Sectional

Spaceflight (SF) has been shown to cause skeletal muscle atrophy; a loss in force and power; and, in the first few weeks, a preferential atrophy of extensors over flexors. The atrophy primarily results from a reduced protein synthesis that is likely triggered by the removal of the antigravity load. Contractile proteins are lost out of proportion to other cellular proteins, and the actin thin filament is lost disproportionately to the myosin thick filament. The decline in contractile protein explains the decrease in force per cross-sectional area, whereas the thin-filament loss may explain the observed postflight increase in the maximal velocity of shortening in the type I and IIa fiber types. Importantly, the microgravity-induced decline in peak power is partially offset by the increased fiber velocity. Muscle velocity is further increased by the microgravity-induced expression of fast-type myosin isozymes in slow fibers (hybrid I/II fibers) and by the increased expression of fast type II fiber types. SF increases the susceptibility of skeletal muscle to damage, with the actual damage elicited during postflight reloading. Evidence in rats indicates that SF increases fatigability and reduces the capacity for fat oxidation in skeletal muscles. Future studies will be required to establish the cellular and molecular mechanisms of the SF-induced muscle atrophy and functional loss and to develop effective exercise countermeasures.

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Amelioration of Muscular Dystrophy by Transgenic Expression of Niemann-Pick C1

Molecular Biology of the Cell ◽

10.1091/mbc.e08-08-0811 ◽

2009 ◽

Vol 20 (1) ◽

pp. 146-152 ◽

Cited By ~ 6

Author(s):

Michelle S. Steen ◽

Marvin E. Adams ◽

Yan Tesch ◽

Stanley C. Froehner

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Molecular Mechanisms ◽

Mdx Mouse ◽

Lysosomal Storage ◽

Transgenic Expression ◽

New Therapeutic Approaches ◽

Human Disorders ◽

Niemann Pick ◽

Dystrophin Protein

Duchenne muscular dystrophy (DMD) and other types of muscular dystrophies are caused by the loss or alteration of different members of the dystrophin protein complex. Understanding the molecular mechanisms by which dystrophin-associated protein abnormalities contribute to the onset of muscular dystrophy may identify new therapeutic approaches to these human disorders. By examining gene expression alterations in mouse skeletal muscle lacking α-dystrobrevin (Dtna−/−), we identified a highly significant reduction of the cholesterol trafficking protein, Niemann-Pick C1 (NPC1). Mutations in NPC1 cause a progressive neurodegenerative, lysosomal storage disorder. Transgenic expression of NPC1 in skeletal muscle ameliorates muscular dystrophy in the Dtna−/− mouse (which has a relatively mild dystrophic phenotype) and in the mdx mouse, a model for DMD. These results identify a new compensatory gene for muscular dystrophy and reveal a potential new therapeutic target for DMD.

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