metallothionein and Muscular-Diseases

Training under hypoxia has several advantages over normoxic training in terms of enhancing the physical performance. Therefore, we tested the protective effect of hypoxia preconditioning by hypoxia mimetic cobalt chloride against exercise-induced oxidative damage in the skeletal muscles and improvement of physical performance.. Male Sprague-Dawley rats were randomly divided into four groups (n=8), namely control, cobalt-supplemented, training and cobalt with training. The red gastrocnemius muscle was examined for all measurements, viz. free radical generation, lipid peroxidation, muscle damage and antioxidative capacity.. Hypoxic preconditioning with cobalt along with training significantly increased physical performance (33%, P<0.01) in rats compared with training-only rats. Cobalt supplementation activated cellular oxygen sensing system in rat skeletal muscle. It also protected against training-induced oxidative damage as observed by an increase in the GSH/GSSG ratio (36%, P<0.001; 28%, P<0.01 respectively) and reduced lipid peroxidation (15%, P<0.01; 31%, P<0.01 respectively) in both trained and untrained rats compared with their respective controls. Cobalt supplementation along with training enhanced the expression of antioxidant proteins haem oxygenase-1 (HO-1; 1.2-fold, P<0.05) and metallothionein (MT; 4.8-fold, P<0.001) compared with training only. A marked reduction was observed in exercise-induced muscle fibre damage as indicated by decreased necrotic muscle fibre, decreased lipofuscin content of muscle and plasma creatine kinase level (16%, P<0.01) in rats preconditioned with cobalt.. Our study provides strong evidence that hypoxic preconditioning with cobalt chloride enhances physical performance and protects muscle from exercise-induced oxidative damage via GSH, HO-1 and MT-mediated antioxidative capacity.

Topics: Animals; Antioxidants; Cell Hypoxia; Cobalt; Creatine Kinase, MM Form; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Heme Oxygenase (Decyclizing); Lactic Acid; Lipid Peroxidation; Lipofuscin; Male; Metallothionein; Mitochondria, Muscle; Mitochondrial Proteins; Muscle, Skeletal; Muscular Diseases; Necrosis; Oxidative Stress; Physical Endurance; Physical Exertion; Rats; Rats, Wistar; Reactive Oxygen Species

Data from individual animals were used to identify genes in mouse skeletal muscle whose expression correlated with a known serum marker of skeletal myopathy, creatine kinase activity (CK), after treatment with a peroxisome proliferator-activated receptors (PPAR) agonist, GW610742X. Six genes had correlation coefficients of >or=0.90: Mt1a (metallothionein 1a), Rrad (Ras-related associated with diabetes), Ankrd1 (ankyrin repeat domain 1), Stat3 (signal transducer and activator of transcription 3), Socs3 (suppressor of cytokine signalling 3) and Mid1ip1 (Mid1 interacting protein 1). The physiological function of these genes provides potentially useful information relating to the mechanism of PPAR-induced skeletal myopathy, with oxidative stress and disruption of glycolysis most closely associated with myopathic damage. Some of the muscle genes most highly correlated with serum CK in mice also appear to be good indicators of PPAR-induced myopathy in rat skeletal muscle, demonstrating the translational potential of this approach. This study clearly shows the utility of using correlation analysis as a simple tool for identifying novel biomarkers and investigating mechanisms of toxicity.

Topics: Animals; Biomarkers; Creatine Kinase; Female; Gene Expression; Gene Expression Profiling; Male; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Proteins; Muscle, Skeletal; Muscular Diseases; Nuclear Proteins; Oligonucleotide Array Sequence Analysis; Peroxisome Proliferator-Activated Receptors; ras Proteins; Rats; Rats, Sprague-Dawley; Repressor Proteins; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Thiazoles