Reduced mitochondrial fission and impaired energy metabolism in human primary skeletal muscle cells of Megaconial Congenital Muscular Dystrophy

Abstract

Megaconial Congenital Muscular Dystrophy (CMD) is a rare autosomal recessive disorder characterized by enlarged mitochondria located mainly at the periphery of muscle fibers and caused by mutations in the Choline Kinase Beta (CHKB) gene. Although the pathogenesis of this disease is not well understood, there is accumulating evidence for the presence of mitochondrial dysfunction. In this study, we aimed to investigate whether imbalanced mitochondrial dynamics affects mitochondrial function and bioenergetic efficiency in skeletal muscle cells of Megaconial CMD. Immunofluorescence, confocal and transmission electron microscopy studies revealed impaired mitochondrial network, morphology, and localization in primary skeletal muscle cells of Megaconial CMD. The organelle disruption was specific only to skeletal muscle cells grown in culture. The expression levels of mitochondrial fission proteins (DRP1, MFF, FIS1) were found to be decreased significantly in both primary skeletal muscle cells and tissue sections of Megaconial CMD by Western blotting and/or immunofluorescence analysis. The metabolomic and fluxomic analysis, which were performed in Megaconial CMD for the first time, revealed decreased levels of phosphonucleotides, Krebs cycle intermediates, ATP, and altered energy metabolism pathways. Our results indicate that reduced mitochondrial fission and altered mitochondrial energy metabolism contribute to mitochondrial dysmorphology and dysfunction in the pathogenesis of Megaconial CMD.

Innately expressed estrogen‐related receptors in the skeletal muscle are indispensable for exercise fitness

“…For example, alterations in mitochondrial DNA are associated with myofiber atrophy and decreased muscle regenerative capacity in sarcopenia 40,41 . Furthermore, muscle wasting in several types of muscular dystrophies is related to loss of mitochondrial and oxidative gene expression and mitochondrial dysfunction 42–44 …”

“…40,41 Furthermore, muscle wasting in several types of muscular dystrophies is related to loss of mitochondrial and oxidative gene expression and mitochondrial dysfunction. [42][43][44] Previous transgenic overexpression studies showed that both ERRs positively regulated the formation of type IIA and IIX (oxidative) myofibers in the skeletal muscle, and suppress the formation of type IIB (glycolytic) myofibers. 10,19 In contrast, deletion of ERRs in the DKO muscles results in an increased type IIA and decreased type IIX myofibers without affecting type IIB myofibers.…”

Statins Induce Locomotion and Muscular Phenotypes in Drosophila melanogaster That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes

“…In contrary, in most TEM micrographs, the control group displayed arranged, aggregated and elongated-shaped mitochondria that occasionally isolate neighbouring myofibrils ( Figure 3 A,B). Given the importance of size and the round shape of the mitochondria in muscle pathologies [ 85 , 86 , 87 , 88 ], we attempted to quantify surface area (size) and count the number of the round-like shaped mitochondria using ImageJ. Interestingly, in contrast to the control group, the fluvastatin-treated flies showed significantly larger mitochondria sizes ( Figure 3 E) and the number of round-like shaped mitochondria was remarkably higher ( Figure 3 F).…”

Complex I, V, and MDH2 deficient human skin fibroblasts reveal distinct metabolic signatures by 1H HR‐MAS NMR

“…Our data shows significantly increased inositol for all defects compared to controls while AMP was generally decreased relative to controls. Since reduced mitochondrial fission is linked to impaired energy metabolism 29 it is possible that the measured inositol and AMP levels in defects are reflective of the reduced OXPHOS activity observed in all defects (cf. OCR levels in Figure 1).…”