Mitochondrial therapy improves limb perfusion and myopathy following hindlimb ischemia. (August 2016)

• Record Type: Journal Article
• Authors: Ryan, Terence E.; Schmidt, Cameron A.; Alleman, Rick J.; Tsang, Alvin M.; Green, Thomas D.; Neufer, P. Darrell; Brown, David A.; McClung, Joseph M.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 97(2016:Aug.)
• Page Start: 191
• Page End: 196
• Publication Date: 2016-08
• Subjects: Ischemia -- Peripheral artery disease -- Critical limb ischemia -- Mitochondria; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2016.05.015
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Critical limb ischemia is a devastating manifestation of peripheral arterial disease with no effective strategies for improving morbidity and mortality outcomes. We tested the hypothesis that cellular mitochondrial function is a key component of limb pathology and that improving mitochondrial function represents a novel paradigm for therapy. BALB/c mice were treated with a therapeutic mitochondrial-targeting peptide (MTP-131) and subjected to limb ischemia (HLI). Compared to vehicle control, MTP-131 rescued limb muscle capillary density and blood flow (64.7 ± 11% of contralateral vs. 39.9 ± 4%), and improved muscle regeneration. MTP-131 also increased electron transport system flux across all conditions at HLI day-7. In vitro, primary muscle cells exposed to experimental ischemia demonstrated markedly reduced (~ 75%) cellular respiration, which was rescued by MTP-131 during a recovery period. Compared to muscle cells, endothelial cell (HUVEC) respiration was inherently protected from ischemia (~ 30% reduction), but was also enhanced by MTP-131. These findings demonstrate an important link between ischemic tissue bioenergetics and limb blood flow and indicate that the mitochondria may be a pharmaceutical target for therapeutic intervention during critical limb ischemia. Highlights: Critical limb ischemia results in severe skeletal muscle mitochondrial myopathy. Mitochondrial dysfunction with ischemia is more severe in muscle compared to endothelial cells. Mitochondrial-targeted peptide therapy improves recovery from limb ischemia.