Small molecule oxybutynin rescues proliferative capacity of complex III-defective MPCs

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 indicates that oxybutynin interacts with a suite of proteins involved in mRNA processing which then trigger the upregulation 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. Overall design: To uncover small molecules that can improve proliferation of complex III defective skeletal muscle myoblasts a small molecule screen of 50 compounds was performed in sol8 cells (treated with antimycin to inhibit complex III). Since oxybutynin showed significant improvements in the proliferation of these cells we then validated its efficacy in murine primary myoblasts from uqcrfs1 floxed mice. Experimental groups included floxed (uqcrfs1+/+) and KO (uqcrfs1-/-) Comparative gene expression profiling was conducted on Uqcrfs1 -/- primary myoblasts that were treated with 7.5uM of oxybutynin for 5 days