TY - JOUR
T1 - Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5
AU - Oikawa, Yoshitsugu
AU - Izumi, Rumiko
AU - Koide, Masashi
AU - Hagiwara, Yoshihiro
AU - Kanzaki, Makoto
AU - Suzuki, Naoki
AU - Kikuchi, Koichi
AU - Matsuhashi, Tetsuro
AU - Akiyama, Yukako
AU - Ichijo, Mariko
AU - Watanabe, Shun
AU - Toyohara, Takafumi
AU - Suzuki, Takehiro
AU - Mishima, Eikan
AU - Akiyama, Yasutoshi
AU - Ogata, Yoshiaki
AU - Suzuki, Chitose
AU - Hayashi, Hironori
AU - Kodama, Eiichi N.
AU - Hayashi, Ken Ichiro
AU - Itoi, Eiji
AU - Aoki, Masashi
AU - Kure, Shigeo
AU - Abe, Takaaki
N1 - Funding Information:
This work was supported in part by a National Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (18H02822) and the Translational Research Network Program (C50) of the Japan Agency for Medical Research and Development (AMED).
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85097121902&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097121902&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0231064
DO - 10.1371/journal.pone.0231064
M3 - Article
C2 - 33264289
AN - SCOPUS:85097121902
VL - 15
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 12 December
M1 - e0231064
ER -