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.

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

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.

Racial differences in the limb skeletal muscle transcriptional programs of patients with critical limb ischemia.

Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease (PAD) and is characterized by high rates of morbidity and mortality. As with most severe cardiovascular disease manifestations, Black individuals disproportionately present with CLI. Accordingly, there remains a clear need to better understand the reasons for this discrepancy and to facilitate personalized therapeutic options specific for this population.

Prescribed exercise to Reduce Recidivism After Weight Loss-Pilot (PREVAIL-P): Design, methods and rationale.

Clinically significant weight loss is associated with health benefits for overweight and obese adults. Participation in adequate amounts of physical activity is critical for weight maintenance. However, the recommended amount of physical activity needed to promote weight maintenance is based primarily on retrospective studies that quantified physical activity levels through questionnaires which tend to overestimate physical activity levels.

PFKFB3-mediated glycolysis rescues myopathic outcomes in the ischemic limb.

Compromised muscle mitochondrial metabolism is a hallmark of peripheral arterial disease, especially in patients with the most severe clinical manifestation - critical limb ischemia (CLI). We asked whether inflexibility in metabolism is critical for the development of myopathy in ischemic limb muscles. Using Polg mtDNA mutator (D257A) mice, we reveal remarkable protection from hind limb ischemia (HLI) due to a unique and beneficial adaptive enhancement of glycolytic metabolism and elevated ischemic muscle PFKFB3.

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.

Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants.

The most severe manifestation of peripheral arterial disease (PAD) is critical limb ischemia (CLI). CLI patients suffer high rates of amputation and mortality; accordingly, there remains a clear need both to better understand CLI and to develop more effective treatments. Gastrocnemius muscle was obtained from 32 older (51-84 years) non-PAD controls, 27 claudicating PAD patients (ankle-brachial index [ABI] 0.

Effects of fish oils on ex vivo B-cell responses of obese subjects upon BCR/TLR stimulation: a pilot study.

The long-chain n-3 polyunsaturated fatty acids (LC-PUFAs) eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) in fish oil have immunomodulatory properties. B cells are a poorly studied target of EPA/DHA in humans. Therefore, in this pilot study, we tested how n-3 LC-PUFAs influence B-cell responses of obese humans.

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.

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).

The Relationship Between Physical Activity and the Metabolic Syndrome Score in Children.

The relationship between physical activity levels and the metabolic syndrome (MetSyn) score was examined in 72 boys and girls (9.5 ± 1.2 years).

Assessment of in vivo skeletal muscle mitochondrial respiratory capacity in humans by near-infrared spectroscopy: a comparison with in situ measurements.

The present study aimed to compare in vivo measurements of skeletal muscle mitochondrial respiratory capacity made using near-infrared spectroscopy (NIRS) with the current gold standard, namely in situ measurements of high-resolution respirometry performed in permeabilized muscle fibres prepared from muscle biopsies. Mitochondrial respiratory capacity was determined in 21 healthy adults in vivo using NIRS to measure the recovery kinetics of muscle oxygen consumption following a ∼15 s isometric contraction of the vastus lateralis muscle. Maximal ADP-stimulated (State 3) respiration was measured in permeabilized muscle fibres using high-resolution respirometry with sequential titrations of saturating concentrations of metabolic substrates.

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.

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.

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.

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.

Iodine-131--metaiodobenzylguanidine double infusion with autologous stem-cell rescue for neuroblastoma: a new approaches to neuroblastoma therapy phase I study.

Purpose: Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) provides targeted radiotherapy with more than 30% response rate in refractory neuroblastoma, but activity infused is limited by radiation safety and hematologic toxicity. The goal was to determine the maximum-tolerated dose of (131)I-MIBG in two consecutive infusions at a 2-week interval, supported by autologous stem-cell rescue (ASCR) 2 weeks after the second dose.

Patients And Methods: The (131)I-MIBG dose was escalated using a 3 + 3 phase I trial design, with levels calculated by cumulative red marrow radiation index (RMI) from both infusions.

Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma.

Purpose: To evaluate the effect of disease sites and prior therapy on response and toxicity after iodine-131-metaiodobenzylguanidine (131I-MIBG) treatment of patients with resistant neuroblastoma.

Patients And Methods: One hundred sixty-four patients with progressive, refractory or relapsed high-risk neuroblastoma, age 2 to 30 years, were treated in a limited institution phase II study. Patients with cryopreserved hematopoietic stem cells (n = 148) were treated with 18 mCi/kg of 131I-MIBG.

Biodistribution of post-therapeutic versus diagnostic (131)I-MIBG scans in children with neuroblastoma.

Background: To evaluate the biodistribution of therapeutic (131)I-metaiodobenzylguanidine (MIBG) and assess the sensitivity of diagnostic versus therapeutic (131)I-MIBG scans to detect metastatic disease.

Procedure: This retrospective study included 44 diagnostic and post-therapy scans (PTS) in 18 children with neuroblastoma treated with (131)I-MIBG (2.0-33.

Targeted radiotherapy with submyeloablative doses of 131I-MIBG is effective for disease palliation in highly refractory neuroblastoma.

Purpose: Treatment of refractory neuroblastoma remains a significant clinical problem. Targeted radiotherapy with 131I-MIBG has demonstrated antitumor activity in heavily pretreated neuroblastoma patients with recurrent disease. Response rates may be correlated with total radionuclide dose per kilogram body weight delivered, but higher dose levels are associated with protracted grade 4 hematologic toxicity.