Muscles Susceptibility to Ischemia-Reperfusion Injuries Depends on Fiber Type Specific Antioxidant Level

Abstract

Muscle injury resulting from ischemia-reperfusion largely aggravates patient prognosis but whether and how muscle phenotype modulates ischemia-reperfusion-induced mitochondrial dysfunction remains to be investigated. We challenged the hypothesis that glycolytic muscles are more prone to ischemia-reperfusion-induced injury than oxidative skeletal muscles. We therefore determined simultaneously the effect of 3 h of ischemia induced by aortic clamping followed by 2 h of reperfusion (IR, n = 11) on both gastrocnemius and soleus muscles, as compared to control animals (C, n = 11). Further, we investigated whether tempol, an antioxidant mimicking superoxide dismutase, might compensate a reduced defense system, likely characterizing glycolytic muscles (IR-Tempol, n = 7). In the glycolytic gastrocnemius muscle, as compared to control, ischemia-reperfusion significantly decreased mitochondrial respiration (−30.28 ± 6.16%, p = 0.003), increased reactive oxygen species production (+79.15 ± 28.72%, p = 0.04), and decreased reduced glutathione (−28.19 ± 6.80%, p = 0.011). Less deleterious effects were observed in the oxidative soleus muscle (−6.44 ± 6.30%, +4.32 ± 16.84%, and −8.07 ± 10.84%, respectively), characterized by enhanced antioxidant defenses (0.63 ± 0.05 in gastrocnemius vs. 1.24 ± 0.08 μmol L−1 g−1 in soleus). Further, when previously treated with tempol, glycolytic muscle was largely protected against the deleterious effects of ischemia-reperfusion. Thus, oxidative skeletal muscles are more protected than glycolytic ones against ischemia-reperfusion, thanks to their antioxidant pool. Such pivotal data support that susceptibility to ischemia-reperfusion-induced injury differs between organs, depending on their metabolic phenotypes. This suggests a need to adapt therapeutic strategies to the specific antioxidant power of the target organ to be protected.

The Rise of Mitochondria in Peripheral Arterial Disease Physiopathology: Experimental and Clinical Data

“…Indeed, mitochondrial respiration was affected by hindlimb ischemia-reperfusion in limb muscles of BALB/c mice, but not of C57BL/6 mice [23]. Secondly, ischemia-reperfusion injury was shown to affect more severely the respiration in glycolytic muscles than in oxidative ones [24]. Furthermore, the impairments in mitochondrial respiration observed in young mice were greater in older animals submitted to ischemia-reperfusion injury [25].…”

Impact of Melatonin on Skeletal Muscle and Exercise

“…Myotubes size Regular Reduced [48,50,57] Satellite cells Present Reduced/Absent [6,42,47] Mitophagy Normal Aberrant [55,59,60,65] Neuromuscular junction Regular Absent [9,10,12,41] Triads/Calcium flux Regular/Present Disrupted/Absent [26,27,49,74] Mitochondria size/number Regular Fission/Fusion Megamitochondria Abnormal Fission/Fusion [32,54,56,66] Inflammation Absent Present [3,52,62,70] ROS formation Absent/Minimal High [53,69,73] ATP production High Limited [61] Microcirculation Effective Disrupted [71,72,74] *ROS, reactive oxygen species.…”

Critical Limb Ischemia Induces Remodeling of Skeletal Muscle Motor Unit and Myonuclear- and Mitochondrial-Domains

“…With the loss of type I fibers in ischemia, it is likely that the majority of myofibers remaining (types IIA, IIB, IIX) decrease their myonuclear domain in response to ischemic insults. Interestingly, oxidative type I fibers have also been shown to be more protected against oxidative stress damage than glycolytic type IIB/IIX fibers in acute ischemia-reperfusion involving a tourniquet [46]. However, since our findings in the more severe form of ischemic injury demonstrate a loss of type I fibers with no change in type II fibers, the type II fibers may have a more robust regenerative ability following atrophy in a chronically ischemic environment.…”