SOD2 in skeletal muscle: New insights from an inducible deletion model
Aowen Zhuang,
Christine Yang,
Yingying Liu,
Yanie Tan,
Simon T. Bond,
Shannen Walker,
Tim Sikora,
Adrienne Laskowski,
Arpeeta Sharma,
Judy B. de Haan,
Peter J. Meikle,
Takahiko Shimizu,
Melinda T. Coughlan,
Anna C. Calkin,
Brian G. Drew
Affiliations
Aowen Zhuang
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia; Central Clinical School, Monash University, Melbourne, 3004, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
Christine Yang
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia
Yingying Liu
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia
Yanie Tan
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia; Central Clinical School, Monash University, Melbourne, 3004, Australia
Simon T. Bond
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia; Central Clinical School, Monash University, Melbourne, 3004, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
Shannen Walker
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia; Central Clinical School, Monash University, Melbourne, 3004, Australia
Tim Sikora
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia
Adrienne Laskowski
Department of Diabetes, Central Clinical School, Monash University, Melbourne, 3004, Australia
Arpeeta Sharma
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia
Judy B. de Haan
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia; Central Clinical School, Monash University, Melbourne, 3004, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, 3083, Australia; Faculty of Science, Engineering and Technology, Swinburne University, Melbourne, 3122, Australia
Peter J. Meikle
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia; Central Clinical School, Monash University, Melbourne, 3004, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
Takahiko Shimizu
Aging Stress Response Research Project Team, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan
Melinda T. Coughlan
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia; Department of Diabetes, Central Clinical School, Monash University, Melbourne, 3004, Australia
Anna C. Calkin
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia; Central Clinical School, Monash University, Melbourne, 3004, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
Brian G. Drew
Baker Heart & Diabetes Institute, Melbourne, 3004, Australia; Central Clinical School, Monash University, Melbourne, 3004, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; Corresponding author. Baker Heart & Diabetes Institute, Melbourne, 3004, Australia.
Metabolic conditions such as obesity, insulin resistance and glucose intolerance are frequently associated with impairments in skeletal muscle function and metabolism. This is often linked to dysregulation of homeostatic pathways including an increase in reactive oxygen species (ROS) and oxidative stress. One of the main sites of ROS production is the mitochondria, where the flux of substrates through the electron transport chain (ETC) can result in the generation of oxygen free radicals. Fortunately, several mechanisms exist to buffer bursts of intracellular ROS and peroxide production, including the enzymes Catalase, Glutathione Peroxidase and Superoxide Dismutase (SOD). Of the latter, there are two intracellular isoforms; SOD1 which is mostly cytoplasmic, and SOD2 which is found exclusively in the mitochondria. Developmental and chronic loss of these enzymes has been linked to disease in several studies, however the temporal effects of these disturbances remain largely unexplored. Here, we induced a post-developmental (8-week old mice) deletion of SOD2 in skeletal muscle (SOD2-iMKO) and demonstrate that 16 weeks of SOD2 deletion leads to no major impairment in whole body metabolism, despite these mice displaying alterations in aspects of mitochondrial abundance and voluntary ambulatory movement. This is likely partly explained by the suggestive data that a compensatory response may exist from other redox enzymes, including catalase and glutathione peroxidases. Nevertheless, we demonstrated that inducible SOD2 deletion impacts on specific aspects of muscle lipid metabolism, including the abundance of phospholipids and phosphatidic acid (PA), the latter being a key intermediate in several cellular signaling pathways. Thus, our findings suggest that post-developmental deletion of SOD2 induces a more subtle phenotype than previous embryonic models have shown, allowing us to highlight a previously unrecognized link between SOD2, mitochondrial function and bioactive lipid species including PA.
