Multiple Mitochondrial Alterations in a Case of Myopathy

Fujioka, Hisashi; Tandler, Bernard; Cohen, Mark L.; Koontz, None Daniel; Hoppel, Charles L.

doi:10.3109/01913123.2014.888114

Cited by 8 publications

(7 citation statements)

References 29 publications

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“…Mitochondrial abnormalities have been described in other muscle diseases such as collagen VI-related myopathies [51,52], muscular dystrophy due to choline kinase beta (CHKB) gene mutations [53], myositis [37], and Duchenne muscular dystrophy [36]. We and others have previously demonstrated that addressing mitochondrial abnormalities in mdx mice can reduce muscle pathology and improve muscle function [43,[54][55][56][57][58]. Thus, our observations suggest an overlap in therapies for muscular dystrophies that improve mitochondrial metabolism.…”

Section: Discussionsupporting

confidence: 51%

Mitochondrial dysfunction and consequences in calpain-3-deficient muscle

et al. 2020

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Background Nonsense or loss-of-function mutations in the non-lysosomal cysteine protease calpain-3 result in limb-girdle muscular dystrophy type 2A (LGMD2A). While calpain-3 is implicated in muscle cell differentiation, sarcomere formation, and muscle cytoskeletal remodeling, the physiological basis for LGMD2A has remained elusive. Methods Cell growth, gene expression profiling, and mitochondrial content and function were analyzed using muscle and muscle cell cultures established from healthy and calpain-3-deficient mice. Calpain-3-deficient mice were also treated with PPAR-delta agonist (GW501516) to assess mitochondrial function and membrane repair. The unpaired t test was used to assess the significance of the differences observed between the two groups or treatments. ANOVAs were used to assess significance over time. Results We find that calpain-3 deficiency causes mitochondrial dysfunction in the muscles and myoblasts. Calpain-3-deficient myoblasts showed increased proliferation, and their gene expression profile showed aberrant mitochondrial biogenesis. Myotube gene expression analysis further revealed altered lipid metabolism in calpain-3-deficient muscle. Mitochondrial defects were validated in vitro and in vivo. We used GW501516 to improve mitochondrial biogenesis in vivo in 7-month-old calpain-3-deficient mice. This treatment improved satellite cell activity as indicated by increased MyoD and Pax7 mRNA expression. It also decreased muscle fatigability and reduced serum creatine kinase levels. The decreased mitochondrial function also impaired sarcolemmal repair in the calpain-3-deficient skeletal muscle. Improving mitochondrial activity by acute pyruvate treatment improved sarcolemmal repair. Conclusion Our results provide evidence that calpain-3 deficiency in the skeletal muscle is associated with poor mitochondrial biogenesis and function resulting in poor sarcolemmal repair. Addressing this deficit by drugs that improve mitochondrial activity offers new therapeutic avenues for LGMD2A.

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Section: Discussionsupporting

confidence: 51%

Mitochondrial dysfunction and consequences in calpain-3-deficient muscle

et al. 2020

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“…Mitochondrial ultrastructure and content were evaluated by transmission electron microscopy as described ( 45 , 46 ). Briefly, cells were seeded onto 0.1% gelatin-coated 0.4-μm polyethylene terephthalate membranes (Falcon) and cultured as described above.…”

Section: Methodsmentioning

confidence: 99%

Dynamin-related protein 1 regulates substrate oxidation in skeletal muscle by stabilizing cellular and mitochondrial calcium dynamics

King

Axelrod

Zunica

et al. 2021

Journal of Biological Chemistry

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Mitochondria undergo continuous cycles of fission and fusion to promote inheritance, regulate quality control, and mitigate organelle stress. More recently, this process of mitochondrial dynamics has been demonstrated to be highly sensitive to nutrient supply, ultimately conferring bioenergetic plasticity to the organelle. However, whether regulators of mitochondrial dynamics play a causative role in nutrient regulation remains unclear. In this study, we generated a cellular loss-of-function model for dynamin-related protein 1 (DRP1), the primary regulator of outer membrane mitochondrial fission. Loss of DRP1 (shDRP1) resulted in extensive ultrastructural and functional remodeling of mitochondria, characterized by pleomorphic enlargement, increased electron density of the matrix, and defective NADH and succinate oxidation. Despite increased mitochondrial size and volume, shDRP1 cells exhibited reduced cellular glucose uptake and mitochondrial fatty acid oxidation. Untargeted transcriptomic profiling revealed severe downregulation of genes required for cellular and mitochondrial calcium homeostasis, which was coupled to loss of ATP-stimulated calcium flux and impaired substrate oxidation stimulated by exogenous calcium. The insights obtained herein suggest that DRP1 regulates substrate oxidation by altering whole-cell and mitochondrial calcium dynamics. These findings are relevant to the targetability of mitochondrial fission and have clinical relevance in the identification of treatments for fission-related pathologies such as hereditary neuropathies, inborn errors in metabolism, cancer, and chronic diseases.

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“…Brains were harvested and sectioned 500 mm-thick (coronally at P7, sagittally at P30) with a vibrating microtome (Leica, Heidelberg, Germany). A 500 mm x 500 mm cube was cut from the corpus callosum above the lateral ventricle where all confocal images were collected and fixed by immersion in triple-aldehyde DMSO (Fujioka et al, 2014a(Fujioka et al, , 2014b. Specimen were thoroughly rinsed in 0.1 M phosphate buffer, pH 7.4, then post-fixed for 2 hours in an unbuffered 1:1 mixture of 2% osmium tetroxide and 3% potassium ferricyanide.…”

Section: Electron Microscopymentioning

confidence: 99%

Fractalkine-Dependent Microglial Pruning of Viable Oligodendrocyte Progenitor Cells Regulates Myelination

2020

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SUMMARY Oligodendrogenesis occurs during early postnatal development, coincident with neurogenesis and synaptogenesis, raising the possibility that microglia-dependent pruning mechanisms that modulate neurons regulate myelin sheath formation. Here we show a population of ameboid microglia migrating from the ventricular zone into the corpus callosum during early postnatal development, termed “the fountain of microglia,” phagocytosing viable oligodendrocyte progenitor cells (OPCs) before onset of myelination. Fractalkine receptor-deficient mice exhibit a reduction in microglial engulfment of viable OPCs, increased numbers of oligodendrocytes, and reduced myelin thickness but no change in axon number. These data provide evidence that microglia phagocytose OPCs as a homeostatic mechanism for proper myelination. A hallmark of hypomyelinating developmental disorders such as periventricular leukomalacia and of adult demyelinating diseases such as multiple sclerosis is increased numbers of oligodendrocytes but failure to myelinate, suggesting that microglial pruning of OPCs may be impaired in pathological states and hinder myelination.

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Multiple Mitochondrial Alterations in a Case of Myopathy

Cited by 8 publications

References 29 publications

Mitochondrial dysfunction and consequences in calpain-3-deficient muscle

Mitochondrial dysfunction and consequences in calpain-3-deficient muscle

Dynamin-related protein 1 regulates substrate oxidation in skeletal muscle by stabilizing cellular and mitochondrial calcium dynamics

Fractalkine-Dependent Microglial Pruning of Viable Oligodendrocyte Progenitor Cells Regulates Myelination

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