Mitochondrial therapy improves limb perfusion and myopathy following hindlimb ischemia.
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.
Department of Physiology, East Carolina University, Brody School of Medicine, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Brody School of Medicine, Greenville, NC, USA.
Terence E
TE
Ryan
Department of Physiology, East Carolina University, Brody School of Medicine, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Brody School of Medicine, Greenville, NC, USA.
Cameron A
CA
Schmidt
Department of Physiology, East Carolina University, Brody School of Medicine, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Brody School of Medicine, Greenville, NC, USA.
Rick J
RJ
Alleman
Department of Physiology, East Carolina University, Brody School of Medicine, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Brody School of Medicine, Greenville, NC, USA.
Alvin M
AM
Tsang
Department of Physiology, East Carolina University, Brody School of Medicine, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Brody School of Medicine, Greenville, NC, USA.
Thomas D
TD
Green
Department of Physiology, East Carolina University, Brody School of Medicine, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Brody School of Medicine, Greenville, NC, USA.
P Darrell
PD
Neufer
Department of Physiology, East Carolina University, Brody School of Medicine, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Brody School of Medicine, Greenville, NC, USA.
David A
DA
Brown
Department of Physiology, East Carolina University, Brody School of Medicine, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Brody School of Medicine, Greenville, NC, USA. Electronic address: mcclungj@ecu.edu.
Joseph M
JM
McClung
D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells; D006614:Hindlimb / Q000098:blood supply* / Q000378:metabolism*; D006801:Humans; D007511:Ischemia / Q000150:complications* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008931:Mitochondria, Muscle / Q000378:metabolism*; D009135:Muscular Diseases / Q000209:etiology* / Q000473:pathology / Q000628:therapy; D009336:Necrosis; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology
D009842:Oligopeptides; D010455:Peptides; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide
Critical limb ischemia; Ischemia; Mitochondria; Peripheral artery disease