This study shows that high intensity training is required for induction of changes in cardiac substrate utilization and energetics, which may contribute to the superior effects of high compared with moderate intensity training in terms of increasing aerobic capacity.

Lund J, Hafstad AD, Boardman NT, Rossvoll L, Rolim NP, Ahmed MS, Florholmen G, Attramadal H, Wisløff U, Larsen TS, Aasum E. Exercise training promotes cardioprotection through oxygen-sparing action in high fat-fed mice. Am J Physiol Heart Circ Physiol 308: H823-H829, 2015. First published January 30, 2015; doi:10.1152/ajpheart.00734.2014.-Although exercise training has been demonstrated to have beneficial cardiovascular effects in diabetes, the effect of exercise training on hearts from obese/diabetic models is unclear. In the present study, mice were fed a high-fat diet, which led to obesity, reduced aerobic capacity, development of mild diastolic dysfunction, and impaired glucose tolerance. Following 8 wk on high-fat diet, mice were assigned to 5 weekly high-intensity interval training (HIT) sessions (10 ϫ 4 min at 85-90% of maximum oxygen uptake) or remained sedentary for the next 10 constitutive weeks. HIT increased maximum oxygen uptake by 13%, reduced body weight by 16%, and improved systemic glucose homeostasis. Exercise training was found to normalize diastolic function, attenuate diet-induced changes in myocardial substrate utilization, and dampen cardiac reactive oxygen species content and fibrosis. These changes were accompanied by normalization of obesity-related impairment of mechanical efficiency due to a decrease in work-independent myocardial oxygen consumption. Finally, we found HIT to reduce infarct size by 47% in ex vivo hearts subjected to ischemia-reperfusion. This study therefore demonstrated for the first time that exercise training mediates cardioprotection following ischemia in diet-induced obese mice and that this was associated with oxygen-sparing effects. These findings highlight the importance of optimal myocardial energetics during ischemic stress. cardiac efficiency; myocardial oxygen consumption; mechanoenergetics; high-intensity exercise; diet-induced obesity THERE HAS BEEN a dramatic transition from physical activity to sedentary lifestyle during the last century. This has resulted in an epidemic increase in the prevalence of metabolic syndrome, obesity, and diabetes, all of which increase the risk of developing cardiovascular and metabolic disorders (15, 42). Cardiovascular diseases are the major causes of morbidity and mortality in type 2 diabetic patients (25) who are at higher risk of developing heart failure, angina, acute myocardial infarction, and dying from an acute myocardial infarction (2).Diabetes-related cardiac complications are due to increased coronary artery disease as well as the development of a specific diabetic cardiomyopathy characterized by ventricular dysfunction in the absence of coronary artery disease or hypertension (24). Although the pathogenesis of diabetes/obesity-related cardiomyopathy is multifactorial and complex, decreased cardiac efficiency seems to play an essential role and is an early hallmark of the diabetic heart (5, 9, 22, 36).Physical training is a well-documented measure to reduce the development of obesity/diabetes, as well as an effec...

Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

Background— Omecamtiv mecarbil (OM) is a novel inotropic agent that prolongs systolic ejection time and increases ejection fraction through myosin ATPase activation. We hypothesized that a potentially favorable energetic effect of unloading the left ventricle, and thus reduction of wall stress, could be counteracted by the prolonged contraction time and ATP-consumption. Methods and Results— Postischemic left ventricular dysfunction was created by repetitive left coronary occlusions in 7 pigs (7 healthy pigs also included). In both groups, systolic ejection time and ejection fraction increased after OM (0.75 mg/kg loading for 10 minutes, followed by 0.5 mg/kg/min continuous infusion). Cardiac efficiency was assessed by relating myocardial oxygen consumption to the cardiac work indices, stroke work, and pressure–volume area. To circumvent potential neurohumoral reflexes, cardiac efficiency was additionally assessed in ex vivo mouse hearts and isolated myocardial mitochondria. OM impaired cardiac efficiency; there was a 31% and 23% increase in unloaded myocardial oxygen consumption in healthy and postischemic pigs, respectively. Also, the oxygen cost of the contractile function was increased by 63% and 46% in healthy and postischemic pigs, respectively. The increased unloaded myocardial oxygen consumption was confirmed in OM-treated mouse hearts and explained by an increased basal metabolic rate. Adding the myosin ATPase inhibitor, 2,3-butanedione monoxide abolished all surplus myocardial oxygen consumption in the OM-treated hearts. Conclusions— Omecamtiv mecarbil, in a clinically relevant model, led to a significant myocardial oxygen wastage related to both the contractile and noncontractile function. This was mediated by that OM induces a continuous activation in resting myosin ATPase.

We have reported previously that hearts from type 2 diabetic (db/db) mice show decreased cardiac efficiency due to increased work-independent myocardial O(2) consumption (unloaded MVo(2)), indicating higher O(2) use for nonmechanical processes such as basal metabolism (MVo(2)(BM)) and excitation-contraction coupling (MVo(2)(ECC)). Although alterations in cardiac metabolism and/or Ca(2+) handling may contribute to increased energy expenditure in diabetic hearts, direct measurements of the O(2) cost for these individual processes have not been determined. In this study, we 1) validate a procedure for measuring unloaded MVo(2) directly (MVo(2)(unloaded)) and for determining MVo(2)(BM) and MVo(2)(ECC) separately in isolated perfused mouse hearts and 2) determine O(2) cost for these processes in hearts from db/db mice. Unloaded MVo(2), extrapolated from the relationship between cardiac work (measured as pressure-volume area, PVA) and MVo(2), was found to correspond with MVo(2) measured directly in unloaded retrograde perfused hearts (MVo(2)(unloaded)). MVo(2) in K(+)-arrested hearts was defined as MVo(2)(BM); the difference between MVo(2)(unloaded) and MVo(2)(BM) represented MVo(2)(ECC). This procedure was validated by demonstrating that elevations in perfusate fatty acid (FA) and/or Ca(2+) concentrations resulted in changes in either MVo(2)(BM) and/or MVo(2)(ECC). The higher MVo(2)(unloaded) in db/db mice was due to both a higher MVo(2)(BM) and MVo(2)(ECC). Elevation of glucose and insulin decreased FA oxidation and reduced both MVo(2)(unloaded) and MVo(2)(BM). In conclusion, this study provides direct evidence that MVo(2)(BM) and MVo(2)(ECC) are elevated in diabetes and that acute metabolic interventions can have a therapeutic benefit in diabetic hearts due to a MVo(2)-lowering effect.