The Effect Of Revascularization On Muscle Mitochondrial Function And Mir-210 Expression In Peripheral Artery Disease

PURPOSE: Peripheral artery disease (PAD) causes a myopathy in the lower extremity muscles, which contributes to patient functional disability. Although mitochondrial dysfunction promotes PAD muscle pathology, the underlying mechanisms are unclear. Recent studies note microRNA (miR)-210, a hypoxia-responsive negative regulator of mitochondrial respiration, is elevated in the blood of PAD patients. Thus, we compared miR-210 expression in skeletal muscle tissue of PAD patients versus non-PAD controls and its association to mitochondrial function and walking ability. The impact of revascularization on muscle miR-210 was also assessed. METHODS: Vascular surgeons at Baylor Scott and White Hospital and the University of Texas Health Science Center at San Antonio harvested gastrocnemius muscle biopsies from non-PAD controls (n = 8), intermittent claudication (IC) patients (n = 10 pre- and post-revascularization) and critical limb ischemia (CLI) patients (n = 12). Muscle miR-210 expression was analyzed by RT-PCR. High-resolution respirometry was used to measure muscle mitochondrial respiration. The six-minute walk test distance (6MWD) was used to assess walking ability. RESULTS: MiR-210 expression was elevated in IC (1.69 ± 0.64-fold, p = 0.14) and CLI (1.88 ± 0.71-fold, p = 0.02) muscle, and mitochondrial respiration was significantly lower during electron transport chain Complex II (p < 0.001 for IC and CLI) and Complex IV (IC: p = 0.04, CLI: p = 0.003), compared to non-PAD controls. MiR-210 expression was also negatively associated with Complex I (R2 = 0.21, p = 0.01), Complex I + II (R2 = 0.33, p = 0.001), and Complex IV respiration (R2 = 0.18, p = 0.01), as well as 6MWD (R2 = 0.57, p < 0.001). In IC patients, revascularization significantly reduced miR-210 expression (0.96 ± 0.19-fold, p < 0.001) and improved mitochondrial respiration of Complexes I + II and IV (p = 0.04), relative to pre-operative levels. CONCLUSION: MiR-210 expression is increased in PAD muscle and may be a critical link in PAD-associated reductions in mitochondrial respiration and walking ability. Thus, miR-210 may represent a novel diagnostic and prognostic biomarker for PAD myopathy, and a potential target for improving mitochondrial function and walking performance in PAD. Supported by NIH Grant R01AG064420.