Skeletal muscle ischemia–reperfusion injury and cyclosporine A in the aging rat

Abstract

Old patients exhibit muscle impairments and increased perioperative risk during vascular surgery procedures. Although aging generally impairs protective mechanisms, data are lacking concerning skeletal muscle in elderly. We tested whether cyclosporine A (CsA), which protects skeletal muscle from ischemia-reperfusion (IR) in young rats, might reduce skeletal muscle mitochondrial dysfunction and oxidative stress in aging rats submitted to hindlimb IR. Wistar rats aged 71-73 weeks were randomized to IR (3 h unilateral tourniquet application and 2 h reperfusion) or IR + CsA (10 mg/kg cyclosporine IV before reperfusion). Maximal oxidative capacity (VM ax ), acceptor control ratio (ACR), and relative contribution of the mitochondrial respiratory chain complexes II, III, IV (VS ucc ), and IV (VTMPD /Asc ), together with calcium retention capacity (CRC) a marker of apoptosis, and tissue reactive oxygen species (ROS) production were determined in gastrocnemius muscles from both hindlimbs. Compared to the nonischemic hindlimb, IR significantly reduced mitochondrial coupling, VMax (from 7.34 ± 1.50 to 2.87 ± 1.22 μMO2 /min/g; P < 0.05; -70%), and VS ucc (from 6.14 ± 1.07 to 3.82 ± 0.83 μMO2 /min/g; P < 0.05; -42%) but not VTMPD /Asc . IR also decreased the CRC from 15.58 ± 3.85 to 6.19 ± 0.86 μMCa(2+) /min/g; P < 0.05; -42%). These alterations were not corrected by CsA (-77%, -49%, and -32% after IR for VM ax, VS ucc , and CRC, respectively). Further, CsA significantly increased ROS production in both hindlimbs (P < 0.05; +73%). In old rats, hindlimb IR impairs skeletal muscle mitochondrial function and increases oxidative stress. Cyclosporine A did not show protective effects.

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

“…Impairments in mitochondrial respiration were observed in both claudicating and CLTI experimental models. Indeed, significant reduction in mitochondrial complexes I, II and IV activities was found in muscles of rats submitted to hindlimb ischemia-reperfusion compared to contralateral muscles [18][19][20][21]. Similarly, mouse models of CLTI presented decreased activities of the complexes I, III and IV in ischemic muscles compared with controls [22].…”

The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore

“…Aging greatly attenuates IRPC (Boengler et al ., ; Fernandez‐Sanz et al ., ). Similarly, cyclosporine A protects from ischemia–reperfusion damage in the young but not in the old (Liu et al ., ; Pottecher et al ., ). It was suggested that the deacetylation of CypD by sirt3 is an important contributor to IRPC (Bochaton et al ., ) and this protection is lost in aged cells because of NAD + depletion, as discussed above.…”

Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology

“…In the past decade, several in vitro and in vivo studies have confirmed the involvement of MPT in ischemia/RI [83]. The administration of CsA (as well as its analog FK506) has been shown to protect against ischemia/RI in multiple animal models and in multiple tissues, including cardiac and skeletal muscle, brain, kidney, liver, lungs, and testis [84][85][86][87][88][89]. Ppif -KO mice are significantly protected from ischemia/RI in both cardiac muscle and the brain, in terms of both tissue function and survival rates [31,32,90].…”