Fletcher 2023 Transl Res

Fletcher E, Miserlis D, Sorokolet K, Wilburn D, Bradley C, Papoutsi E, Wilkinson T, Ring A, Ferrer L, Haynatzki G, Smith RS, Bohannon WT, Koutakis P (2023) Diet-induced obesity augments ischemic myopathy and functional decline in a murine model of peripheral artery disease. https://doi.org/10.1016/j.trsl.2023.05.002

» Transl Res 260:17-31. PMID: 37220835 Open Access

Fletcher Emma, Miserlis Dimitrios, Sorokolet Kristina, Wilburn Dylan, Bradley Cassandra, Papoutsi Evlampia, Wilkinson Trevor, Ring Andrew, Ferrer Lucas, Haynatzki Gleb, Smith Robert S, Bohannon William T, Koutakis Panagiotis (2023) Transl Res

Abstract: Peripheral artery disease (PAD) causes an ischemic myopathy contributing to patient disability and mortality. Most preclinical models to date use young, healthy rodents with limited translatability to human disease. Although PAD incidence increases with age, and obesity is a common comorbidity, the pathophysiologic association between these risk factors and PAD myopathy is unknown. Using our murine model of PAD, we sought to elucidate the combined effect of age, diet-induced obesity and chronic hindlimb ischemia (HLI) on (1) mobility, (2) muscle contractility, and markers of muscle (3) mitochondrial content and function, (4) oxidative stress and inflammation, (5) proteolysis, and (6) cytoskeletal damage and fibrosis. Following 16-weeks of high-fat, high-sucrose, or low-fat, low-sucrose feeding, HLI was induced in 18-month-old C57BL/6J mice via the surgical ligation of the left femoral artery at 2 locations. Animals were euthanized 4-weeks post-ligation. Results indicate mice with and without obesity shared certain myopathic changes in response to chronic HLI, including impaired muscle contractility, altered mitochondrial electron transport chain complex content and function, and compromised antioxidant defense mechanisms. However, the extent of mitochondrial dysfunction and oxidative stress was significantly greater in obese ischemic muscle compared to non-obese ischemic muscle. Moreover, functional impediments, such as delayed post-surgical recovery of limb function and reduced 6-minute walking distance, as well as accelerated intramuscular protein breakdown, inflammation, cytoskeletal damage, and fibrosis were only evident in mice with obesity. As these features are consistent with human PAD myopathy, our model could be a valuable tool to test new therapeutics. • Keywords: Obesity, Age, Ischemic myopathy, Mitochondriopathy, Peripheral artery disease • Bioblast editor: Plangger M • O2k-Network Lab: US TX Waco Koutakis P

Labels: MiParea: Respiration  Pathology: Myopathy, Obesity 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase 

Coupling state: LEAK, OXPHOS  Pathway: N, S, DQ, CIV, NS, ROX  HRR: Oxygraph-2k, O2k-Fluorometer 

2023-07, AmR