Optic atrophy 1 mediates muscle differentiation by promoting a metabolic switch via the supercomplex assembly factor SCAF1
Matthew Triolo,
Nicole Baker,
Soniya Agarwal,
Nikita Larionov,
Tina Podinić,
Mireille Khacho
Affiliations
Matthew Triolo
Department of Biochemistry, Microbiology and Immunology, Center for Neuromuscular Disease (CNMD), Ottawa Institute of Systems Biology (OISB), Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Nicole Baker
Department of Biochemistry, Microbiology and Immunology, Center for Neuromuscular Disease (CNMD), Ottawa Institute of Systems Biology (OISB), Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Soniya Agarwal
Department of Biochemistry, Microbiology and Immunology, Center for Neuromuscular Disease (CNMD), Ottawa Institute of Systems Biology (OISB), Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Nikita Larionov
Department of Biochemistry, Microbiology and Immunology, Center for Neuromuscular Disease (CNMD), Ottawa Institute of Systems Biology (OISB), Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Tina Podinić
Department of Biochemistry, Microbiology and Immunology, Center for Neuromuscular Disease (CNMD), Ottawa Institute of Systems Biology (OISB), Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Mireille Khacho
Department of Biochemistry, Microbiology and Immunology, Center for Neuromuscular Disease (CNMD), Ottawa Institute of Systems Biology (OISB), Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Corresponding author
Summary: Myogenic differentiation is integral for the regeneration of skeletal muscle following tissue damage. Though high-energy post-mitotic muscle relies predominantly on mitochondrial respiration, the importance of mitochondrial remodeling in enabling muscle differentiation and the players involved are not fully known. Here we show that the mitochondrial fusion protein OPA1 is essential for muscle differentiation. Our study demonstrates that OPA1 loss or inhibition, through genetic and pharmacological means, abolishes in vivo muscle regeneration and in vitro myotube formation. We show that both the inhibition and genetic deletion of OPA1 prevent the early onset metabolic switch required to drive myoblast differentiation. In addition, we observe an OPA1-dependent upregulation of the supercomplex assembly factor, SCAF1, at the onset of differentiation. Importantly, preventing the upregulation of SCAF1, through OPA1 loss or siRNA-mediated SCAF1 knockdown, impairs metabolic reprogramming and muscle differentiation. These findings reveal the integral role of OPA1 and mitochondrial reprogramming at the onset of myogenic differentiation.
