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

Julien Pottecher, Michel Kindo, Thiên Nga Chamaraux-Tran, Anne Laure Charles, Anne Lejay, Véronique Kemmel, Thomas Vogel, Nabil Chakfe, Joffrey Zoll, Pierre Diemunsch, Bernard Geny

Research output: Contribution to journalArticle

9 Scopus citations

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 (VMax), acceptor control ratio (ACR), and relative contribution of the mitochondrial respiratory chain complexes II, III, IV (VSucc), 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 VSucc (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 μMCa2+/min/g; P < 0.05; -42%). These alterations were not corrected by CsA (-77%, -49%, and -32% after IR for VMax, VSucc, 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.

Original languageEnglish (US)
Pages (from-to)216-225
Number of pages10
JournalFundamental and Clinical Pharmacology
Volume30
Issue number3
DOIs
StatePublished - Jun 1 2016

Keywords

  • Aging
  • Cyclosporine
  • Ischemia-reperfusion injury
  • Mitochondria
  • Oxidative stress
  • Skeletal muscle

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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