Targeted Expression of Catalase to Mitochondria Protects Against Ischemic Myopathy in High-Fat Diet-Fed Mice.
Patients with type 2 diabetes respond poorly to treatments for peripheral arterial disease (PAD) and are more likely to present with the most severe manifestation of the disease, critical limb ischemia. The underlying mechanisms linking type 2 diabetes and the severity of PAD manifestation are not well understood. We sought to test whether diet-induced mitochondrial dysfunction and oxidative stress would increase the susceptibility of the peripheral limb to hindlimb ischemia (HLI). Six weeks of high-fat diet (HFD) in C57BL/6 mice was insufficient to alter skeletal muscle mitochondrial content and respiratory function or the size of ischemic lesion after HLI, despite reducing blood flow. However, 16 weeks of HFD similarly decreased ischemic limb blood flow, but also exacerbated limb tissue necrosis, increased the myopathic lesion size, reduced muscle regeneration, attenuated muscle function, and exacerbated ischemic mitochondrial dysfunction. Mechanistically, mitochondrial-targeted overexpression of catalase prevented the HFD-induced ischemic limb necrosis, myopathy, and mitochondrial dysfunction, despite no improvement in limb blood flow. These findings demonstrate that skeletal muscle mitochondria are a critical pathological link between type 2 diabetes and PAD. Furthermore, therapeutically targeting mitochondria and oxidant burden is an effective strategy to alleviate tissue loss and ischemic myopathy during PAD.
East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC.
Terence E
TE
Ryan
East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC.
Cameron A
CA
Schmidt
East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC.
Thomas D
TD
Green
East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC.
Espen E
EE
Spangenburg
East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC.
P Darrell
PD
Neufer
East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC mcclungj@ecu.edu.
Joseph M
JM
McClung
D000818:Animals; D001823:Body Composition / Q000502:physiology; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005951:Glucose Tolerance Test; D006614:Hindlimb / Q000473:pathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007511:Ischemia / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000201:enzymology*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009135:Muscular Diseases / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D010084:Oxidation-Reduction; D058729:Peripheral Arterial Disease / Q000517:prevention & control
D006861:Hydrogen Peroxide; D002374:Catalase