d-arg-dmt-lys-phe-nh2 and Muscular-Atrophy

Spinal cord injury (SCI) leads to rapid muscle atrophy due to paralysis/paresis and subsequent disuse. SS-31 is a mitochondrial-targeting peptide that has shown efficacy in protecting skeletal muscle mass and function in non-SCI models of muscle wasting. We aimed to determine if SS-31 could prevent muscle loss after SCI. Male C57BL/6 mice aged 9 weeks underwent sham surgery or 50 kdyne contusion SCI and were administered daily injections of vehicle or 5 mg/kg SS-31 for 14 d. Both SCI groups had sustained losses in body mass compared to Sham animals and ~10% reductions in gastrocnemius, plantaris and tibialis anterior muscle mass after SCI with no clear effect of SS-31. Measurements of protein synthesis in the soleus and plantaris were similar among all groups. mRNA expression of atrophy-associated proinflammatory cytokines was also similar among all groups. There was elevation in MYH7 mRNA and a statistical reduction in MYH2 mRNA expression in the SCI+SS-31 animals compared to Sham animals. There was an SCI-induced reduction in mRNA expression of the E3 ligase FBXO32 (MAFbx), but no effect of SS-31. In summary, a 50 kdyne contusion SCI was able to reduce body mass but was not associated with substantial muscle atrophy or alterations in gene expression profiles associated with muscle health and function 14 d post-injury. SS-31 was not associated with protection against SCI-related changes in body or muscle mass, protein synthesis or gene expression in hindlimb muscles.

Topics: Animals; Body Composition; Cell Line; Disease Models, Animal; Gene Expression Regulation; Male; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Atrophy; Oligopeptides; Spinal Cord Injuries; Time Factors

Mechanical ventilation is a life-saving intervention used to provide adequate pulmonary ventilation in patients suffering from respiratory failure. However, prolonged mechanical ventilation is associated with significant diaphragmatic weakness resulting from both myofiber atrophy and contractile dysfunction. Although several signaling pathways contribute to diaphragm weakness during mechanical ventilation, it is established that oxidative stress is required for diaphragmatic weakness to occur. Therefore, identifying the site(s) of mechanical ventilation- induced reactive oxygen species production in the diaphragm is important.. These experiments tested the hypothesis that elevated mitochondrial reactive oxygen species emission is required for mechanical ventilation-induced oxidative stress, atrophy, and contractile dysfunction in the diaphragm.. Cause and effect was determined by preventing mechanical ventilation-induced mitochondrial reactive oxygen species emission in the diaphragm of rats using a novel mitochondria-targeted antioxidant (SS-31).. None.. Compared to mechanically ventilated animals treated with saline, animals treated with SS-31 were protected against mechanical ventilation-induced mitochondrial dysfunction, oxidative stress, and protease activation in the diaphragm. Importantly, treatment of animals with the mitochondrial antioxidant also protected the diaphragm against mechanical ventilation-induced myofiber atrophy and contractile dysfunction.. These results reveal that prevention of mechanical ventilation-induced increases in diaphragmatic mitochondrial reactive oxygen species emission protects the diaphragm from mechanical ventilation-induced diaphragmatic weakness. This important new finding indicates that mitochondria are a primary source of reactive oxygen species production in the diaphragm during prolonged mechanical ventilation. These results could lead to the development of a therapeutic intervention to impede mechanical ventilation-induced diaphragmatic weakness.

Topics: Actins; Animals; Calpain; Caspase 3; Diaphragm; Female; Hydrogen Peroxide; Mitochondria, Muscle; Muscle Contraction; Muscle Fibers, Skeletal; Muscle Proteins; Muscle Weakness; Muscular Atrophy; Oligopeptides; Oxidative Stress; Rats; Rats, Sprague-Dawley; Respiration, Artificial; SKP Cullin F-Box Protein Ligases; Tripartite Motif Proteins; Ubiquitin-Protein Ligases

Topics: Animals; Diaphragm; Humans; Mitochondria, Muscle; Muscle Contraction; Muscle Weakness; Muscular Atrophy; Oligopeptides; Oxidative Stress; Rats; Respiration, Artificial