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S ‐nitrosylation of Mitochondrial Proteins Preserves Skeletal Muscle Function From Ischemia‐Reperfusion‐Induced Injury
Author(s) -
Wilson Rebecca June,
Zhang Mei,
Murphy Michael P.,
Yan Zhen
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.742.5
Subject(s) - skeletal muscle , mitochondrion , nitric oxide , ischemia , reperfusion injury , chemistry , medicine , reactive oxygen species , oxidative phosphorylation , endogeny , biochemistry , endocrinology , pharmacology
Ischemia‐reperfusion (IR) injury in skeletal muscle is a common complication in many diseases and clinical settings that leads to loss of muscle mass and function. Unfortunately, there are currently no preemptive treatments to reduce IR injury in skeletal muscle. Generation of mitochondrial reactive oxygen species (ROS) during rapid re‐establishment of oxidative phosphorylation in mitochondria upon reperfusion has been identified as a major mediator of IR injury in skeletal muscle. We hypothesized that reversible suppression of mitochondrial respiration by covalently linking nitric oxide moieties to protein thiols ( S‐ nitrosylation or SNO), which is known to inhibit enzyme activities, may mitigate IR injury to skeletal muscle. We subjected C57BL/6 mice to 1 hour of unilateral ischemia by application of a rubber‐band tourniquet or to a sham procedure (Con). Five minutes prior to tourniquet removal, we performed intramuscular injection of an endogenous s‐nitrosothiol (S‐ nitrosoglutathione, GSNO group), a mitochondria‐specific S ‐nitrosothiol (MitoSNO1 group) or the respective vehicles (IR group). We assessed muscle weight and maximal specific force production 14 days following IR injury. The IR group had significantly less muscle force than Con mice (~50% reduction), while GSNO injection led to a moderate, but not statistically significant improvement of muscle force compared to the IR group (~10% improvement). Treatment with MitoSNO1 resulted in a complete recovery of muscle force. Gastrocnemius and tibialis anterior muscle masses were significantly reduced by ~40% and ~20%, respectively, in the IR and GSNO groups, but preserved in the MitoSNO1 group. Taken together, targeted S‐ nitrosylation of mitochondrial proteins profoundly protects skeletal muscle against IR injury‐induced loss in muscle mass and function. Therefore, mitochondria targeted interventions may provide an efficacious means for protection of skeletal muscle against IR injury. Support or Funding Information AHA Predoctoral Award #14PRE20380254