Abstract
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.
Highlights
Sporadic inclusion body myositis is the most common idiopathic inflammatory myopathy in individuals over the age of 50 years [1], and it is distinguished from other idiopathic inflammatory myopathies by early asymmetric finger flexor and knee extensor weakness, which leads to the loss of hand function and a propensity to fall [2]
Rimmed vacuoles are commonly detected in muscle tissue from patients with mitochondrial myopathy [5]. 2) Ragged-red fibers and cytochrome oxidase (COX)-negative fibers, both of which are specific to mitochondrial disease [6], are observed in Sporadic inclusion body myositis (sIBM) [4, 7]. 3) Mitochondrial DNA deletions have been reported in sIBM [8, 9]
We report the presence of mitochondrial dysfunction in sIBM and that a mitochondriahoming drug, Mitochonic acid-5 (MA-5), may be a potential candidate drug for sIBM
Summary
Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy in individuals over the age of 50 years [1], and it is distinguished from other idiopathic inflammatory myopathies by early asymmetric finger flexor and knee extensor weakness, which leads to the loss of hand function and a propensity to fall [2]. We recently reported a new mitochondria-homing drug, mitochonic acid-5 (MA-5) (4[2,4-difluorophenyl]-2-[1H-indole-3-yl]-4-oxobutanoic acid), which increases the cellular ATP level and reduces mitochondrial reactive oxygen species (mtROS) production, protecting patients with mitochondrial dysfunction from fibroblast death [10,11,12]. It prolongs the survival of a mouse model of mitochondrial disease [11]. MA-5 improved cell survival, increased ATP, and improved mitochondrial morphology and dynamics, suggesting the potential of MA-5 for sIBM therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
