No abstract

The only known function of NAD(P)H oxidases is to produce reactive oxygen species (ROS). Skeletal muscles express three isoforms of NAD(P)H oxidases (Nox1, Nox2, and Nox4) that have been identified as critical modulators of redox homeostasis. Nox2 acts as the main source of skeletal muscle ROS during contractions, participates insulin signaling and glucose transport, and mediates the myocyte response to osmotic stress. Nox2 and Nox4 contribute to skeletal muscle abnormalities elicited by angiotensin II, muscular dystrophy, heart failure, and high fat diet. Our review addresses the expression and regulation of NAD(P)H oxidases with emphasis on aspects that are relevant to skeletal muscle. We also summarize: i) the most widely used NAD(P)H oxidases activity assays and inhibitors, and ii) studies that have defined Nox enzymes as protagonists of skeletal muscle redox homeostasis in a variety of health and disease conditions.

During the past several decades, the incidence of exertional heat stroke (EHS) has increased dramatically. Despite an improved understanding of this syndrome, numerous controversies still exist within the scientific and health professions regarding diagnosis, pathophysiology, risk factors, treatment, and return to physical activity. This review examines the following eight controversies: 1) reliance on core temperature for diagnosing and assessing severity of EHS; 2) hypothalamic damage induces heat stroke and this mediates “thermoregulatory failure” during the immediate recovery period; 3) EHS is a predictable condition primarily resulting from overwhelming heat stress; 4) heat-induced endotoxemia mediates systemic inflammatory response syndrome in all EHS cases; 5) nonsteroidal anti-inflammatory drugs for EHS prevention; 6) EHS shares similar mechanisms with malignant hyperthermia; 7) cooling to a specific body core temperature during treatment for EHS; and 8) return to physical activity based on physiological responses to a single-exercise heat tolerance test. In this review, we present and discuss the origins and the evidence for each controversy and propose next steps to resolve the misconception.

Diaphragm muscle weakness in chronic heart failure (CHF) is caused by elevated oxidants and exacerbates breathing abnormalities, exercise intolerance, and dyspnea. However, the specific source of oxidants that cause diaphragm weakness is unknown. We examined whether mitochondrial reactive oxygen species (ROS) cause diaphragm weakness in CHF by testing the hypothesis that CHF animals treated with a mitochondria-targeted antioxidant have normal diaphragm function. Rats underwent CHF or sham surgery. Eight weeks after surgeries, we administered a mitochondrial-targeted antioxidant (MitoTEMPO; 1 mg·kg(-1)·day(-1)) or sterile saline (Vehicle). Left ventricular dysfunction (echocardiography) pre- and posttreatment and morphological abnormalities were consistent with the presence of CHF. CHF elicited a threefold (P < 0.05) increase in diaphragm mitochondrial H2O2 emission, decreased diaphragm glutathione content by 23%, and also depressed twitch and maximal tetanic force by ∼20% in Vehicle-treated animals compared with Sham (P < 0.05 for all comparisons). Diaphragm mitochondrial H2O2 emission, glutathione content, and twitch and maximal tetanic force were normal in CHF animals receiving MitoTEMPO. Neither CHF nor MitoTEMPO altered the diaphragm protein levels of antioxidant enzymes: superoxide dismutases (CuZn-SOD or MnSOD), glutathione peroxidase, and catalase. In both Vehicle and MitoTEMPO groups, CHF elicited a ∼30% increase in cytochrome c oxidase activity, whereas there were no changes in citrate synthase activity. Our data suggest that elevated mitochondrial H2O2 emission causes diaphragm weakness in CHF. Moreover, changes in protein levels of antioxidant enzymes or mitochondrial content do not seem to mediate the increase in mitochondria H2O2 emission in CHF and protective effects of MitoTEMPO.