Small molecule oxybutynin rescues proliferative capacity of complex III-defective muscle progenitor cells.

Mitochondrial disease encompasses a group of genetically inherited disorders hallmarked by an inability of the respiratory chain to produce sufficient ATP. These disorders present with multisystemic pathologies that predominantly impact highly energetic tissues such as skeletal muscle. There is no cure or effective treatment for mitochondrial disease. We have discovered a small molecule known as oxybutynin that can bypass complex III mitochondrial dysfunction in primary murine and human skeletal muscle progenitor cells (MPCs). Oxybutynin administration improves MPC proliferative capacity, enhances cellular glycolytic function, and improves myotube formation. Mechanistically, results from our isothermal shift assay indicate that oxybutynin interacts with a suite of proteins involved in mRNA processing, which then trigger the upregulation of biological pathways to circumvent CIII mitochondrial dysfunction. Taken together, we provide evidence for the small molecule oxybutynin as a potential therapeutic candidate for the future treatment of CIII mitochondrial dysfunction.NEW & NOTEWORTHY Mitochondrial disease currently has no cure and affects highly energetic tissues such as skeletal muscle. Under disease conditions, the stem cell pool of the tissue is depleted and has reduced regenerative capacity, resulting in functional decline of the muscle. Here, we have identified the small molecule oxybutynin as a potential treatment option, as it improved the regenerative capacity of skeletal muscle stem cells harboring a complex III mitochondrial disease mutation.