Rationale Mitochondrial dysfunction has been implicated in several cardiovascular diseases; however, the roles of mitochondrial oxidative stress and DNA damage in hypertensive cardiomyopathy are not well understood. Objective We evaluated the contribution of mitochondrial reactive oxygen species (ROS) to cardiac hypertrophy and failure by using genetic mouse models overexpressing catalase targeted to mitochondria and to peroxisomes. Methods and Results Angiotensin II increases mitochondrial ROS in cardiomyocytes, concomitant with increased mitochondrial protein carbonyls, mitochondrial DNA deletions, increased autophagy and signaling for mitochondrial biogenesis in hearts of Angiotensin II treated mice. The causal role of mitochondrial ROS in Angiotensin II-induced cardiomyopathy is shown by the observation that mice that overexpress catalase targeted to mitochondria, but not mice that overexpress wild-type peroxisomal catalase, are resistant to cardiac hypertrophy, fibrosis and mitochondrial damage induced by Angiotensin II, as well as heart failure induced by overexpression of Gαq. Furthermore, primary damage to mitochondrial DNA, induced by zidovudine administration or homozygous mutation of mitochondrial polymerase gamma, is also shown to contribute directly to the development of cardiac hypertrophy, fibrosis and failure. Conclusions These data indicate the critical role of mitochondrial ROS in cardiac hypertrophy and failure and support the potential use of mitochondrial-targeted antioxidants for prevention and treatment of hypertensive cardiomyopathy.

New molecular and in vivo findings regarding the onset and reversibility of mitochondrial dysfunction with age indicate the potential: 1) for diagnostic tools to identify patients at risk for severe irreversible defects later in life; and 2) of an intervention to delay the tempo of aging and improve the quality of life of the elderly.

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Monodelphis domestica (Marsupialia: Didelphidae) was used as a model animal to investigate and compare muscle adaptation to exercise training and cold exposure. The experimental treatment consisted of four groups of animals: either warm or cold acclimation temperature and with or without endurance exercise training. Maximal aerobic capacity during a running VO2max test in the warm-exercised or cold-exposed (with or without exercise) groups was about 130 mL O(2)/kg/min, significantly higher than the warm-acclimated controls at 113.5 mL O(2)/kg/min. Similarly, during an acute cold challenge (VO2summit), maximal aerobic capacity was higher in these three experimental groups at approximately 95 mL O(2)/kg/min compared with 80.4 mL O(2)/kg/min in warm-acclimated controls. Respiratory exchange ratio was significantly lower (0.89-0.68), whereas relative heart mass (0.52%-0.73%) and whole-body muscle mitochondrial volume density (2.59 to 3.04 cm(3)) were significantly higher following cold exposure. Chronic cold exposure was a stronger stimulus than endurance exercise training for tissue-specific adaptations. Although chronic cold exposure and endurance exercise are distinct challenges, physiological adaptations to each overlap such that the capacities for aerobic performance in response to both cold exposure and running are increased by either or both treatments.

control or exercise-trained animals, indicating greater oxidative capacity. Finally, we identified an uncoupling protein 3 homologue, whose gene expression was upregulated in skeletal muscle of cold-exposed Monodelphis domestica. Cold exposure provided a potent stimulus for muscle plasticity, driving a fast-to-slow transition more effectively than exercise training. However, linked to the dramatic shift in muscle properties is an equally dramatic increase in whole animal muscle energetics during locomotion, suggesting an uncoupled state, or 'training for inefficiency'.