Mitochondrial therapy improves limb perfusion and myopathy following hindlimb ischemia

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.

BAG3 (Bcl-2–Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy

“…The degree of tissue necrosis in Congenic mice mirrored that of parental BL6 mice, indicating that BL6-encoded variants in this region contributed to muscle survival. Histological analysis of ischemic limb muscle largely revealed a restoration of ischemic muscle (L) fascicular and vascular morphology compared to the contralateral limb (R) (Figure 1B), which we have previously observed in BL6 but not BALB/c mice 44–46 . Myofiber integrity (non-myofiber area), regeneration (embryonic MyHC + ), and capillary density (CD31 + ) were all similar in the ischemic limbs of Congenic and BL6 mice but were significantly different from those in BALB/c mice (Figure 1C–E).…”

Disruption of mitochondrial quality control in peripheral artery disease: New therapeutic opportunities

“…Pre-clinical studies using an in vivo mouse model of hindlimb ischemia demonstrate that either permeabilized skinned muscle fibers or mitochondria isolated from ischemic limb (mainly skeletal muscle myocytes) display reduced oxygen consumption as compared with contralateral control limb (28, 46, 47). Moreover, changes in mitochondrial bioenergetics are accompanied by oxidative stress, increased mitochondrial mass, decreased cross-sectional area and myofiber derangement in the ischemic limb (28).…”

“…Recently, pre-clinical studies provide evidence that reduction of mitochondrial oxidative stress protects skeletal muscle (mainly myocytes) against hindlimb ischemia (46, 47). Ryan et al, found that mitochondrial target overexpression of catalase [an enzyme that converts hydrogen peroxide to water and oxygen] improves skeletal muscle morphology, contractility and mitochondrial bioenergetics in obese C57BL/6 mice underwent hindlimb ischemia (47).…”

“…Another paper from the same group demonstrated that sustained treatment using a mitochondrial-target antioxidant peptide increases limb blood flow, skeletal muscle regeneration and mitochondrial function in BALB/c mice subjected to hindlimb ischemia (46). The individual impact of mitochondrial target-antioxidant peptide on skeletal muscle and endothelium cells was validated in culture.…”

“…The individual impact of mitochondrial target-antioxidant peptide on skeletal muscle and endothelium cells was validated in culture. Peptide admnistration protected both primary myotubes and HUVEC (human umbilical vein endothelial cells) mitochondrial bioenergetics against hypoxia-reoxygenation stress (46). Both studies demonstrate that improving mitochondrial redox balance is critical to protect skeletal muscle environment against ischemia-reperfusion injury in rodents.…”