Journal Article

Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5

Aoki, Masashi, Hagiwara, Yoshihiro, Itoi, Eiji, Suzuki, Takehiro, Kure, Shigeo, Ogata, Yoshiaki, Oikawa, Yoshitsugu, Ichijo, Mariko, Abe, Takaaki, Hayashi, Ken-ichiro, Matsuhashi, Tetsuro, Akiyama, Yukako, Kodama, Eiichi N., Kanzaki, Makoto, Izumi, Rumiko, Akiyama, Yasutoshi, Suzuki, Chitose, Hayashi, Hironori, Toyohara, Takafumi, Mishima, Eikan, Suzuki, Naoki, Koide, Masashi, Kikuchi, Koichi, Watanabe, Shun

2020

Overview

Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Abnormalities / Adenosine Triphosphate - biosynthesis / Aged / Aged, 80 and over / ATP / Bioenergetics / Biology / Biology and Life Sciences / Biomedical engineering / Biopsy / Buthionine Sulfoximine - pharmacology / Cell Survival - drug effects / Cells, Cultured / Cytology / Deoxyribonucleic acid / DNA / DNA, Mitochondrial - genetics / Drug Evaluation, Preclinical / Drug therapy / Dynamins - biosynthesis / Dynamins - genetics / Endocrinology / Engineering / Etiology / Female / Fibroblast Growth Factors - blood / Fibroblasts / Fibroblasts - drug effects / Gene expression / Growth Differentiation Factor 15 - biosynthesis / Growth Differentiation Factor 15 - blood / Growth Differentiation Factor 15 - genetics / GTP Phosphohydrolases - biosynthesis / GTP Phosphohydrolases - genetics / Humans / Indoleacetic Acids - pharmacology / Indoleacetic Acids - therapeutic use / Infectious diseases / Inflammation / Inflammatory diseases / Male / Medicine / Medicine and Health Sciences / Middle Aged / Mitochondria / Mitochondria, Muscle - metabolism / Mitochondria, Muscle - pathology / Mitochondrial DNA / Morphology / Musculoskeletal diseases / Myoblasts / Myoblasts - drug effects / Myoblasts - metabolism / Myoblasts - ultrastructure / Myopathy / Myositis / Myositis, Inclusion Body - drug therapy / Myositis, Inclusion Body - metabolism / Myositis, Inclusion Body - pathology / Nephrology / Neurology / Orthopedics / Oxidative stress / Oxygen Consumption / Patients / Pediatrics / Penicillin / Phenylbutyrates - pharmacology / Phenylbutyrates - therapeutic use / Physiological aspects / Reactive Oxygen Species - metabolism / Research and Analysis Methods / Retrospective Studies / University graduates