High-dose atorvastatin therapy progressively decreases skeletal muscle mitochondrial respiratory capacity in humans.

BACKGROUNDWhile the benefits of statin therapy on atherosclerotic cardiovascular disease are clear, patients often experience mild to moderate skeletal myopathic symptoms, the mechanism for which is unknown. This study investigated the potential effect of high-dose atorvastatin therapy on skeletal muscle mitochondrial function and whole-body aerobic capacity in humans.METHODSEight overweight (BMI, 31.9 ± 2.0) but otherwise healthy sedentary adults (4 females, 4 males) were studied before (day 0) and 14, 28, and 56 days after initiating atorvastatin (80 mg/d) therapy.RESULTSMaximal ADP-stimulated respiration, measured in permeabilized fiber bundles from muscle biopsies taken at each time point, declined gradually over the course of atorvastatin treatment, resulting in > 30% loss of skeletal muscle mitochondrial oxidative phosphorylation capacity by day 56. Indices of in vivo muscle oxidative capacity (via near-infrared spectroscopy) decreased by 23% to 45%. In whole muscle homogenates from day 0 biopsies, atorvastatin inhibited complex III activity at midmicromolar concentrations, whereas complex IV activity was inhibited at low nanomolar concentrations.CONCLUSIONThese findings demonstrate that high-dose atorvastatin treatment elicits a striking progressive decline in skeletal muscle mitochondrial respiratory capacity, highlighting the need for longer-term dose-response studies in different patient populations to thoroughly define the effect of statin therapy on skeletal muscle health.FUNDINGNIH R01 AR071263.

Effects of weight loss and weight loss maintenance on cardiac autonomic function in obesity: a randomized controlled trial.

NOVELTY: Caloric restriction and exercise exert significant improvements in cardiac autonomic function as measured by HRV in overweight and obesity. Aerobic exercise training, within recommended guidelines coupled with weight loss maintenance, retains cardiac autonomic function benefits from weight loss in previously obese individuals.

The Effect of Aerobic Training and Increasing Nonexercise Physical Activity on Cardiometabolic Risk Factors.

PURPOSE: Epidemiological studies suggest that sedentary behavior is an independent risk factor for cardiovascular mortality independent of meeting physical activity guidelines. However, limited evidence of this relationship is available from prospective interventions. The purpose of the present study is to evaluate the combined effect of aerobic training and increasing nonexercise physical activity on body composition and cardiometabolic risk factors. METHODS: Obese adults (N = 45) were randomized to 6 months of aerobic training (AERO), aerobic training and increasing nonexercise physical activity (~3000 steps above baseline levels; AERO-PA), or a control (CON) group. The AERO and AERO-PA groups performed supervised aerobic training (3-4 times per week). The AERO-PA group wore Fitbit One accelerometers and received behavioral coaching to increase nonexercise physical activity. RESULTS: There was a larger increase in fitness in the AERO-PA group (0.27 L·min-1; confidence interval (CI), 0.16 to 0.40 L·min-1) compared with the AERO group (0.09 L·min-1; CI, -0.04 to 0.22 L·min-1) and the CON group (0.01; CI, -0.11 to 0.12 L·min-1). Although significant findings were not observed in the entire study sample, when the analysis was restricted to participants compliant to the intervention (n = 33), we observed significant reductions in waist circumference, percent weight loss, body fat, 2-h glucose, and 2-h insulin in comparison to the CON group (P < 0.05), but not the AERO group. Furthermore, linear regression models showed that change in steps was associated with 21% and 26% of the variation in percent weight loss and percent fat loss, respectively. CONCLUSIONS: Increasing nonexercise physical activity with aerobic training may represent a viable strategy to augment the fitness response in comparison to aerobic training alone and has promise for other health indicators.

High-intensity exercise to promote accelerated improvements in cardiorespiratory fitness (HI-PACE): study protocol for a randomized controlled trial.

BACKGROUND: African Americans have a disproportionate prevalence and incidence of type 2 diabetes compared with Caucasians. Recent evidence indicates that low cardiorespiratory fitness (CRF) level, an independent risk factor for type 2 diabetes, is also more prevalent in African Americans than Caucasians. Numerous studies in Caucasian populations suggest that vigorous exercise intensity may promote greater improvements in CRF and other type 2 diabetes risk factors (e.g., reduction of glucose/insulin levels, pulse wave velocity, and body fat) than moderate intensity. However, current evidence comparing health benefits of different aerobic exercise intensities on type 2 diabetes risk factors in African Americans is negligible. This is clinically important as African Americans have a greater risk for type 2 diabetes and are less likely to meet public health recommendations for physical activity than Caucasians. The purpose of the HI-PACE (High-Intensity exercise to Promote Accelerated improvements in CardiorEspiratory fitness) study is to evaluate whether high-intensity aerobic exercise elicits greater improvements in CRF, insulin action, and arterial stiffness than moderate-intensity exercise in African Americans. METHODS/DESIGN: A randomized controlled trial will be performed on overweight and obese (body mass index of 25-45 kg/m2) African Americans (35-65 years) (n = 60). Participants will be randomly assigned to moderate-intensity (MOD-INT) or high-intensity (HIGH-INT) aerobic exercise training or a non-exercise control group (CON) for 24 weeks. Supervised exercise will be performed at a heart rate associated with 45-55% and 70-80% of VO2 max in the MOD-INT and HIGH-INT groups, respectively, for an exercise dose of 600 metabolic equivalents of task (MET)-minutes per week (consistent with public health recommendations). The primary outcome is change in CRF. Secondary outcomes include change in insulin sensitivity (measured via an intravenous glucose tolerance test), skeletal muscle mitochondrial oxidative capacity (via near-infrared spectroscopy), skeletal muscle measurements (i.e., citrate synthase, COX IV, GLUT-4, CPT-1, and PGC1-α), arterial stiffness (via carotid-femoral pulse wave velocity), body fat, C-reactive protein, and psychological outcomes (quality of life/exercise enjoyment). DISCUSSION: The anticipated results of the HI-PACE study will provide vital information on the health effects of high-intensity exercise in African Americans. This study will advance health disparity research and has the potential to influence future public health guidelines for physical activity. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02892331 . Registered on September 8, 2016.

Greater Oxidative Capacity in Primary Myotubes from Endurance-trained Women.

PURPOSE: Exercise training promotes skeletal muscle mitochondrial biogenesis and an increase in maximal oxygen consumption. Primary myotubes retain some metabolic properties observed in vivo but it is unknown whether this includes exercise-induced mitochondrial adaptations. The goal of this study was to test if primary myotubes from exercise-trained women have higher mitochondrial content and maximal oxygen consumption compared with untrained women. METHODS: Six trained and nine untrained white women participated in this study. Muscle biopsies from the vastus lateralis muscle of the right leg were obtained and primary muscle cells were isolated. Maximal respiration rates, mitochondrial mRNA and protein content, and succinate dehydrogenase activity were measured in skeletal muscle and primary myotubes from trained and untrained women. RESULTS: Trained women, compared with untrained women, had higher maximal whole-body oxygen consumption (+18%, P = 0.03), in vivo maximal skeletal muscle oxidative capacity measured with near infrared spectroscopy (+48%, P < 0.01), and maximal oxygen consumption in permeabilized muscle fibers (+38%, P = 0.02), which coincided with higher protein levels of muscle mitochondrial enzymes. Primary myotubes from trained women had higher maximal oxygen consumption (+38%, P = 0.03), suggesting that some elements of exercise-induced metabolic programming persists ex vivo. Consistent with this idea, myotubes from trained women had higher mRNA levels of transcriptional regulators of mitochondrial biogenesis in addition to higher protein levels of mitochondrial enzymes. CONCLUSIONS: These data suggest the existence of an "exercise metabolic program," where primary myotubes isolated from exercise-trained individuals exhibit greater mitochondrial content and oxidative capacity compared with untrained individuals. These myotubes may be a useful model to study molecular mechanisms relevant to exercise adaptations in human skeletal muscle.

The intervention composed of aerobic training and non-exercise physical activity (I-CAN) study: Rationale, design and methods.

Recent data has suggested that prolonged sedentary behavior is independent risk factor for cardiovascular and all-cause mortality independent of adequate amounts of moderate to vigorous physical activity. However, few studies have prospectively evaluated if exercise training and increasing non-exercise physical activity leads to greater reduction in cardiometabolic risk compared to aerobic training alone. The purpose of the Intervention Composed of Aerobic Training and Non-Exercise Physical Activity (I-CAN) study is to determine whether a physical activity program composed of both aerobic training (consistent with public health recommendations) and increasing non-exercise physical activity (3000 steps above baseline levels) leads to enhanced improvements in waist circumference, oral glucose tolerance, systemic inflammation, body composition, and fitness compared to aerobic training alone in obese adults (N=45). Commercially available accelerometers (Fitbits) will be used to monitor physical activity levels and behavioral coaching will be used to develop strategies of how to increase non-exercise physical activity levels. In this manuscript, we describe the design, rationale, and methodology associated with the I-CAN study.

Mitochondrial respiratory capacity and content are normal in young insulin-resistant obese humans.

Considerable debate exists about whether alterations in mitochondrial respiratory capacity and/or content play a causal role in the development of insulin resistance during obesity. The current study was undertaken to determine whether such alterations are present during the initial stages of insulin resistance in humans. Young (∼23 years) insulin-sensitive lean and insulin-resistant obese men and women were studied. Insulin resistance was confirmed through an intravenous glucose tolerance test. Measures of mitochondrial respiratory capacity and content as well as H(2)O(2) emitting potential and the cellular redox environment were performed in permeabilized myofibers and primary myotubes prepared from vastus lateralis muscle biopsy specimens. No differences in mitochondrial respiratory function or content were observed between lean and obese subjects, despite elevations in H(2)O(2) emission rates and reductions in cellular glutathione. These findings were apparent in permeabilized myofibers as well as in primary myotubes. The results suggest that reductions in mitochondrial respiratory capacity and content are not required for the initial manifestation of peripheral insulin resistance.

Comparison of a field-based test to estimate functional threshold power and power output at lactate threshold.

It has been proposed that field-based tests (FT) used to estimate functional threshold power (FTP) result in power output (PO) equivalent to PO at lactate threshold (LT). However, anecdotal evidence from regional cycling teams tested for LT in our laboratory suggested that PO at LT underestimated FTP. It was hypothesized that estimated FTP is not equivalent to PO at LT. The LT and estimated FTP were measured in 7 trained male competitive cyclists (VO2max = 65.3 ± 1.6 ml O2·kg(-1)·min(-1)). The FTP was estimated from an 8-minute FT and compared with PO at LT using 2 methods; LT(Δ1), a 1 mmol·L(-1) or greater rise in blood lactate in response to an increase in workload and LT(4.0), blood lactate of 4.0 mmol·L(-1). The estimated FTP was equivalent to PO at LT(4.0) and greater than PO at LT(Δ1). VO2max explained 93% of the variance in individual PO during the 8-minute FT. When the 8-minute FT PO was expressed relative to maximal PO from the VO2max test (individual exercise performance), VO2max explained 64% of the variance in individual exercise performance. The PO at LT was not related to 8-minute FT PO. In conclusion, FTP estimated from an 8-minute FT is equivalent to PO at LT if LT(4.0) is used but is not equivalent for all methods of LT determination including LT(Δ1).

Inhibiting myosin-ATPase reveals a dynamic range of mitochondrial respiratory control in skeletal muscle.

Assessment of mitochondrial ADP-stimulated respiratory kinetics in PmFBs (permeabilized fibre bundles) is increasingly used in clinical diagnostic and basic research settings. However, estimates of the Km for ADP vary considerably (~20-300 µM) and tend to overestimate respiration at rest. Noting that PmFBs spontaneously contract during respiration experiments, we systematically determined the impact of contraction, temperature and oxygenation on ADP-stimulated respiratory kinetics. BLEB (blebbistatin), a myosin II ATPase inhibitor, blocked contraction under all conditions and yielded high Km values for ADP of >~250 and ~80 µM in red and white rat PmFBs respectively. In the absence of BLEB, PmFBs contracted and the Km for ADP decreased ~2-10-fold in a temperature-dependent manner. PmFBs were sensitive to hyperoxia (increased Km) in the absence of BLEB (contracted) at 30 °C but not 37 °C. In PmFBs from humans, contraction elicited high sensitivity to ADP (Km<100 µM), whereas blocking contraction (+BLEB) and including a phosphocreatine/creatine ratio of 2:1 to mimic the resting energetic state yielded a Km for ADP of ~1560 µM, consistent with estimates of in vivo resting respiratory rates of <1% maximum. These results demonstrate that the sensitivity of muscle to ADP varies over a wide range in relation to contractile state and cellular energy charge, providing evidence that enzymatic coupling of energy transfer within skeletal muscle becomes more efficient in the working state.

Progesterone increases skeletal muscle mitochondrial H2O2 emission in nonmenopausal women.

The luteal phase of the female menstrual cycle is associated with both 1) elevated serum progesterone (P4) and estradiol (E2), and 2) reduced insulin sensitivity. Recently, we demonstrated a link between skeletal muscle mitochondrial H(2)O(2) emission (mE(H2O2)) and insulin resistance. To determine whether serum levels of P4 and/or E(2) are related to mitochondrial function, mE(H2O2) and respiratory O(2) flux (Jo(2)) were measured in permeabilized myofibers from insulin-sensitive (IS, n = 24) and -resistant (IR, n = 8) nonmenopausal women (IR = HOMA-IR > 3.6). Succinate-supported mE(H2O2) was more than 50% greater in the IR vs. IS women (P < 0.05). Interestingly, serum P4 correlated positively with succinate-supported mE(H2O2) (r = 0. 53, P < 0.01). To determine whether P4 or E2 directly affect mitochondrial function, saponin-permeabilized vastus lateralis myofibers biopsied from five nonmenopausal women in the early follicular phase were incubated in P4 (60 nM), E2 (1.4 nM), or both. P4 alone inhibited state 3 Jo(2), supported by multisubstrate combination (P < 0.01). However, E2 alone or in combination with P4 had no effect on Jo(2). In contrast, during state 4 respiration, supported by succinate and glycerophosphate, mE(H2O2) was increased with P4 alone or in combination with E2 (P < 0.01). The results suggest that 1) P4 increases mE(H2O2) with or without E2; 2) P4 alone inhibits Jo(2) but not when E2 is present; and 3) P4 is related to the mE(H2O2) previously linked to skeletal muscle insulin resistance.