Skeletal Muscle Mitochondrial Oxidative Capacity Research Articles

The whole-body and skeletal muscle metabolic response to 14 days of highly controlled low energy availability in endurance-trained females.

This study investigated the effects of 14 days low energy availability (LEA) versus optimal energy availability (OEA) in endurance-trained females on substrate utilization, insulin sensitivity, and skeletal muscle mitochondrial oxidative capacity; and the impact of metabolic changes on exercise performance. Twelve endurance-trained females (V̇O2max 55.2 ± 5.1 mL × min-1 × kg-1) completed two 14-day randomized, blinded, cross-over, controlled dietary interventions: (1) OEA (51.9 ± 2.0 kcal × kg fat-free mass (FFM)-1 × day-1) and (2) LEA (22.3 ± 1.5 kcal × kg FFM-1 × day-1), followed by 3 days OEA. Participants maintained their exercise training volume during both interventions (approx. 8 h × week-1 at 79% heart rate max). Skeletal muscle mitochondrial respiratory capacity, glycogen, and maximal activity of CS, HAD, and PFK were unaltered with LEA. 20-min time trial endurance performance was impaired by 7.8% (Δ -16.8 W, 95% CI: -23.3 to -10.4, p < .001) which persisted following 3 days refueling post-LEA (p < .001). Fat utilization was increased post-LEA as evidenced by: (1) 99.4% (p < .001) increase in resting plasma free fatty acids (FFA); (2) 270% (p = .007) larger reduction in FFA in response to acute exercise; and (3) 28.2% (p = .015) increase in resting fat oxidation which persisted during submaximal exercise (p < .001). These responses were reversed with 3 days refueling. Daily glucose control (via CGM), HOMA-IR, HOMA-β, were unaffected by LEA. Skeletal muscle O2 utilization and carbohydrate availability were not limiting factors for aerobic exercise capacity and performance; therefore, whether LEA per se affects aspects of training quality/recovery requires investigation.

Skeletal muscle mitochondrial correlates of critical power and W' in healthy active individuals.

The asymptote (critical power; CP) and curvature constant (W') of the hyperbolic power-duration relationship can predict performance within the severe-intensity exercise domain. However, the extent to which these parameters relate to skeletal muscle mitochondrial content and respiratory function is not known. Fifteen males (peak O2 uptake, 52.2±8.7mLkg-1min-1; peak work rate, 366±40W; and gas exchange threshold, 162±41W) performed three to five constant-load tests to task failure for the determination of CP (246±44W) and W' (18.6±4.1kJ). Skeletal muscle biopsies were obtained from the vastus lateralis to determine citrate synthase (CS) activity, as a marker of mitochondrial content, and the ADP-stimulated respiration (P) and maximal electron transfer (E) through mitochondrial complexes (C) I-IV. The CP was positively correlated with CS activity (absolute CP, r=0.881, P<0.001; relative CP, r=0.751, P=0.001). The W' was not correlated with CS activity (P>0.05). Relative CP was positively correlated with mass-corrected CI+IIE (r=0.659, P=0.038), with absolute CP being inversely correlated with CS activity-corrected CIVE (r=-0.701, P=0.024). Relative W' was positively correlated with CS activity-corrected CI+IIP (r=0.713, P=0.021) and the phosphorylation control ratio (r=0.661, P=0.038). There were no further correlations between CP or W' and mitochondrial respiratory variables. These findings support the assertion that skeletal muscle mitochondrial oxidative capacity is positively associated with CP and that this relationship is strongly determined by mitochondrial content.

Role of Cardiorespiratory Fitness and Mitochondrial Oxidative Capacity in Reduced Walk Speed of Older Adults With Diabetes.

Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults. The impact of cardiorespiratory fitness and mitochondrial oxidative capacity on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes as well as determine their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n=159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles when compared to those without diabetes (n=717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. 4-m and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walk speed between older adults with and without diabetes. Additional adjustments with BMI and co-morbidities further explained the group differences in walk speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes.

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.

Exploring the links of skeletal muscle mitochondrial oxidative capacity, physical functionality, and mental well-being of cancer survivors

Physical impairments following cancer treatment have been linked with the toxic effects of these treatments on muscle mass and strength, through their deleterious effects on skeletal muscle mitochondrial oxidative capacity. Accordingly, we designed the present study to explore relationships of skeletal muscle mitochondrial oxidative capacity with physical performance and perceived cancer-related psychosocial experiences of cancer survivors. We assessed skeletal muscle mitochondrial oxidative capacity using in vivo phosphorus-31 magnetic resonance spectroscopy (31P MRS), measuring the postexercise phosphocreatine resynthesis time constant, τPCr, in 11 post-chemotherapy participants aged 34–70 years. During the MRS procedure, participants performed rapid ballistic knee extension exercise to deplete phosphocreatine (PCr); hence, measuring the primary study outcome, which was the recovery rate of PCr (τPCr). Patient-reported outcomes of psychosocial symptoms and well-being were assessed using the Patient-Reported Outcomes Measurement Information System and the 36-Item Short Form health survey (SF-36). Rapid bioenergetic recovery, reflected through a smaller value of τPCr was associated with worse depression (rho ρ = − 0.69, p = 0.018, and Cohen’s d = − 1.104), anxiety (ρ = − 0.61, p = .046, d = − 0.677), and overall mental health (ρ = 0.74, p = 0.010, d = 2.198) scores, but better resilience (ρ = 0.65, p = 0.029), and coping-self efficacy (ρ = 0.63, p = 0.04) scores. This is the first study to link skeletal muscle mitochondrial oxidative capacity with subjective reports of cancer-related behavioral toxicities. Further investigations are warranted to confirm these findings probing into the role of disease status and personal attributes in these preliminary results.

Reproducibility of NIRS-derived mitochondrial oxidative capacity in highly active older adults

IntroductionIn-vivo techniques using near-infrared spectroscopy (NIRS) have been developed to assess skeletal muscle mitochondrial oxidative capacity. However, the test-retest and day-to-day reliability of NIRS-derived mitochondrial oxidative capacity has yet to be established in older individuals. Therefore, the primary aim of this study was to determine the day-to-day and test-retest reliability of NIRS-derived mitochondrial oxidative capacity in older adults. The secondary aim was to examine the relationship between NIRS-derived mitochondrial capacity and whole-body aerobic fitness. Material and methodsTwenty-four healthy individuals (19 M, 5F; aged 60 ± 4 years; maximal oxygen uptake (V̇O2peak) = 41.2 ± 6.8 ml.kg−1.min−1) completed three visits to the laboratory. Visit one assessed isometric maximal voluntary contractions of the knee extensors and aerobic capacity through an incremental exercise test. In visits two and three participants completed two measurements of NIRS-derived mitochondrial oxidative capacity in the vastus lateralis (VL). ResultsNIRS-derived mitochondrial oxidative capacity was found to have good to excellent day-to-day reliability (Day 1 vs Day 2; coefficient of variation (CV) = 7.0 %; standard error of measurement (SEM) = 5.2; intra-class correlation coefficient (ICC) = 0.94) and test re-test reliability (Day 1 [Test 1 vs Test 2]; CV = 5.0 %; SEM = 3.7; ICC 0.97 and Day 2 [Test 1 vs Test 2]; CV = 6.3 %; SEM = 4.9; ICC = 0.93). NIRS-derived mitochondrial oxidative capacity was found to be significantly correlated with V̇O2peak (r = −0.61; R2 = 0.37; P = 0.002), oxygen uptake at the gas exchange threshold (r = −0.49; R2 = 0.24; P = 0.02), and oxygen uptake at the respiratory compensation point (r = −0.57; R2 = 0.32; P = 0.004). ConclusionNIRS provides a reliable method for deriving a measure of VL mitochondrial oxidative capacity in highly active older adults and demonstrates a significant relationship with measures of whole-body aerobic fitness.

Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on substrate metabolism in prediabetic insulin resistant individuals: A randomized, double-blind crossover trial

Aims/hypothesisSodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment in type 2 diabetes mellitus patients results in glucosuria, causing an energy loss, and triggers beneficial metabolic adaptations. It is so far unknown if SGLT2i exerts beneficial metabolic effects in prediabetic insulin resistant individuals, yet this is of interest since SGLT2is also reduce the risk for progression of heart failure and chronic kidney disease in patients without diabetes. MethodsFourteen prediabetic insulin resistant individuals (BMI: 30.3 ± 2.1 kg/m2; age: 66.3 ± 6.2 years) underwent 2-weeks of treatment with dapagliflozin (10 mg/day) or placebo in a randomized, placebo-controlled, cross-over design. Outcome parameters include 24-hour and nocturnal substrate oxidation, and twenty-four-hour blood substrate and insulin levels. Hepatic glycogen and lipid content/composition were measured by MRS. Muscle biopsies were taken to measure mitochondrial oxidative capacity and glycogen and lipid content. ResultsDapagliflozin treatment resulted in a urinary glucose excretion of 36 g/24-h, leading to a negative energy and fat balance. Dapagliflozin treatment resulted in a higher 24-hour and nocturnal fat oxidation (p = 0.043 and p = 0.039, respectively), and a lower 24-hour carbohydrate oxidation (p = 0.048). Twenty-four-hour plasma glucose levels were lower (AUC; p = 0.016), while 24-hour free fatty acids and nocturnal β-hydroxybutyrate levels were higher (AUC; p = 0.002 and p = 0.012, respectively) after dapagliflozin compared to placebo. Maximal mitochondrial oxidative capacity was higher after dapagliflozin treatment (dapagliflozin: 87.6 ± 5.4, placebo: 78.1 ± 5.5 pmol/mg/s, p = 0.007). Hepatic glycogen and lipid content were not significantly changed by dapagliflozin compared to placebo. However, muscle glycogen levels were numerically higher in the afternoon in individuals on placebo (morning: 332.9 ± 27.9, afternoon: 368.8 ± 13.1 nmol/mg), while numerically lower in the afternoon on dapagliflozin treatment (morning: 371.7 ± 22.8, afternoon: 340.5 ± 24.3 nmol/mg). Conclusions/interpretationDapagliflozin treatment of prediabetic insulin resistant individuals for 14 days resulted in significant metabolic adaptations in whole-body and skeletal muscle substrate metabolism despite being weight neutral. Dapagliflozin improved fat oxidation and ex vivo skeletal muscle mitochondrial oxidative capacity, mimicking the effects of calorie restriction. Trial registrationClinicalTrials.gov NCT03721874.

Robust arm and leg muscle adaptation to training despite ACE inhibition: a randomized placebo-controlled trial.

Angiotensin-converting enzyme (ACE) inhibitor treatment is widely applied, but the fact that plasma ACE activity is a potential determinant of training-induced local muscular adaptability is often neglected. Thus, we investigated the hypothesis that ACE inhibition modulates the response to systematic aerobic exercise training on leg and arm muscular adaptations. Healthy, untrained, middle-aged participants (40 ± 7 yrs) completed a randomized, double-blinded, placebo-controlled trial. Participants were randomized to placebo (PLA: CaCO3) or ACE inhibitor (ACEi: enalapril) for 8weeks and completed a supervised, high-intensity exercise training program. Muscular characteristics in the leg and arm were extensively evaluated pre and post-intervention. Forty-eight participants (nACEi = 23, nPLA = 25) completed the trial. Exercise training compliance was above 99%. After training, citrate synthase, 3-hydroxyacyl-CoA dehydrogenase and phosphofructokinase maximal activity were increased in m. vastus lateralis in both groups (all P < 0.05) without statistical differences between them (all time × treatment P > 0.05). In m. deltoideus, citrate synthase maximal activity was upregulated to a greater extent (time × treatment P < 0.05) in PLA (51 [33;69] %) than in ACEi (28 [13;43] %), but the change in 3-hydroxyacyl-CoA dehydrogenase and phosphofructokinase maximal activity was similar between groups. Finally, the training-induced changes in the platelet endothelial cell adhesion molecule-1 protein abundance, a marker of capillary density, were similar in both groups in m. vastus lateralis and m. deltoideus. Eight weeks of high-intensity whole-body exercise training improves markers of skeletal muscle mitochondrial oxidative capacity, glycolytic capacity and angiogenesis, with no overall effect of pharmacological ACE inhibition in healthy adults.

534-P: Sustained Improvement of Whole-Body Oxidative Capacity but Not Insulin Sensitivity after Detraining of People with Type 2 Diabetes

High-intensity interval training (HIIT) improves skeletal muscle mitochondrial oxidative capacity in humans with different degrees of insulin sensitivity, whereas it increases insulin sensitivity along with number of circulating small extracellular vesicle (SEV) mainly in insulin resistant individuals with or without T2D (T2D, IR) . In order to examine the sustainability of metabolic effects induced by HIIT, this study tested whether the observed effects on insulin sensitivity, oxidative capacity and SEV number remain and/or differ between insulin sensitive (IS) , IR and T2D humans. Twenty T2D and age- and BMI-matched IR and 12 IS individuals (HbA1c in %: 7.2±0.2, 5.4±0.1, 5.4±0.1; M-value in mg*kg-1*min-1: 3.0±0.4, 4.2±0.4, 7.4±0.4) performed a 12-week HIIT cycling protocol for 3 d/week. Whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps, physical fitness (VO2max) by spiroergometry and myocellular pathways of insulin sensitivity by immunoblotting of muscle biopsies at baseline, 72 h after the last HIIT bout and 4 weeks (detraining) later. SEV were isolated from serum by size exclusion chromatography. Compared to HIIT, insulin sensitivity decreased in T2D after detraining (p&amp;lt;0.01) , instead VO2max decreased in T2D and IR (p&amp;lt;0. and p&amp;lt;0.05) , although it remained higher than baseline (p&amp;lt;0.0 and p=0.05) . Of note, HIIT-induced reduction of the nuclear factor-κB protein (p&amp;lt;0.vs. baseline) disappeared in IR after detraining, whereas decreased protein kinase Cε activity was sustained in T2D (p&amp;lt;0.vs. HIIT and p&amp;lt;0.vs. baseline) , who also showed higher circulating SEV number (p&amp;lt;0.vs. baseline) . In conclusion, HIIT-induced increases in physical fitness and SEV number, but not insulin sensitivity are maintained at least after short-term detraining in T2D. Characterization of SEV cargo might help to better understand the differences in metabolic responses to detraining in individuals with and without T2D Disclosure L.Mastrototaro: None. J.Szendroedi: Advisory Panel; Boehringer Ingelheim International GmbH. M.Roden: Advisory Panel; Eli Lilly and Company, Research Support; Boehringer Ingelheim International GmbH, Nutricia, Speaker's Bureau; Novo Nordisk. M.Apostolopoulou: n/a. N.Saatmann: None. C.Granata: None. S.Hartwig: None. Y.Karusheva: None. S.Gancheva: None. S.Lehr: None. H.Al-hasani: Consultant; Bayer AG.

Disruption of neuromedin B receptor improves mitochondrial oxidative phosphorylation capacity in gastrocnemius muscle of female mice.

Neuromedin B (NB), a bombesin-like peptide, exerts its specific actions by binding to the neuromedin B receptor (NBR), a G protein-coupled receptor. Female NBR-knockout (NBR-KO) mice exhibit resistance to diet-induced obesity, without hyperphagia, suggesting possible increase in energy expenditure. Skeletal muscle (SM) is crucial for whole body energy homeostasis, however, the presence of NB-NBR signaling and its effects in SM are unknown. Here, we show that male and female wild type express Nmbr and Nmb mRNA in SM, with higher levels in females. Female NBR-KO gastrocnemius showed increased Myh7 mRNA level, which characterizes type I fibers (oxidative profile). Their permeabilized gastrocnemius fibers, studied by high-resolution respirometry, exhibited higher consumption of O2 coupled to ATP synthesis and unaltered uncoupled respiration. NBR-KO gastrocnemius had higher protein levels of ATP-synthase and Nduf9 mRNA, corresponding to mitochondrial complex I subunit. NBR-KO gastrocnemius exhibited slight increase in mitochondria number, increased thickness of Z line at electron microscopy, and unaltered mitochondrial dynamics markers. Therefore, in the females' gastrocnemius, a predominantly glycolytic SM, the NBR absence promotes changes that favor mitochondrial oxidative phosphorylation capacity. In addition, in L6 myocytes, NB treatment (5 μg/mL/16 h) promoted lower O2 consumption coupled to ATP synthesis, suggesting direct action at SM cells. Altogether, the study reinforces the hypothesis that inhibition of NB-NBR signaling enhances the capacity for oxidative phosphorylation of white SM, encouraging future studies to elucidate their contribution on other types of SM and whole body energy expenditure, which may lead to a new target to drug development for obesity treatment.NEW & NOTEWORTHY This study describes neuromedin B (NB) and NB receptor as new regulators of skeletal muscle mitochondrial function. The white skeletal muscle mitochondrial oxidative phosphorylation capacity was increased by NB receptor genetic disruption in female mice. These findings may contribute to the resistance to diet-induced obesity, previously found in these mice, which requires future studies. Thus, investigations are necessary to clarify if blockade of NB receptor may be an approach to develop drugs to combat obesity.

Short-Term Adaptations in Skeletal Muscle Mitochondrial Oxidative Capacity and Metabolic Pathways to Breaking up Sedentary Behaviors in Overweight or Obese Adults.

Breaking up sedentary behavior with short-frequent bouts of physical activity (PA) differentially influences metabolic health compared with the performance of a single-continuous bout of PA matched for total active time. However, the underlying mechanisms are unknown. We compared skeletal muscle mitochondrial respiration (high-resolution respirometry) and molecular adaptations (RNA sequencing) following 4-day exposure to breaks vs. energy-matched single-continuous PA bout in inactive adults with overweight/obesity. Participants (9M/10F, 32.2 ± 6.4 years, 30.3 ± 3.0 kg/m2) completed three 4-day interventions of a randomized cross-over study: SED, sedentary control; MICRO, 5 min brisk walking each hour for 9 h; ONE: 45 min/d continuous brisk walking bout. Fasted muscle biopsies were collected on day 5. Mitochondrial coupling in the presence of lipid-associated substrates was higher after ONE (4.8 ± 2.5) compared to MICRO (3.1 ± 1.1, p = 0.02) and SED (2.3 ± 1.0, p = 0.001). Respiratory rates did not differ across groups with carbohydrate-associated substrates. In pathways associated with muscle contraction transcription signaling, ONE and MICRO similarly enhanced Oxidative Phosphorylation and Sirtuin Signaling expression (p < 0.0001, for both). However, ONE (p < 0.001, for all), but not MICRO, had greater pathway enrichment, including Ca++, mTOR, AMPK, and HIF1α signaling, than SED. Although breaking up sedentary behavior triggered skeletal muscle molecular adaptations favoring oxidative capacity, it did not improve mitochondrial function over the short term.

Adipose tissue macrophage populations and inflammation are associated with systemic inflammation and insulin resistance in obesity.

Obesity is accompanied by numerous systemic and tissue-specific derangements, including systemic inflammation, insulin resistance, and mitochondrial abnormalities in skeletal muscle. Despite growing recognition that adipose tissue dysfunction plays a role in obesity-related disorders, the relationship between adipose tissue inflammation and other pathological features of obesity is not well-understood. We assessed macrophage populations and measured the expression of inflammatory cytokines in abdominal adipose tissue biopsies in 39 nondiabetic adults across a range of body mass indexes (BMI 20.5-45.8 kg/m2). Skeletal muscle biopsies were used to evaluate mitochondrial respiratory capacity, ATP production capacity, coupling, and reactive oxygen species production. Insulin sensitivity (SI) and β cell responsivity were determined from test meal postprandial glucose, insulin, c-peptide, and triglyceride kinetics. We examined the relationships between adipose tissue inflammatory markers, systemic inflammatory markers, SI, and skeletal muscle mitochondrial physiology. BMI was associated with increased adipose tissue and systemic inflammation, reduced SI, and reduced skeletal muscle mitochondrial oxidative capacity. Adipose-resident macrophage numbers were positively associated with circulating inflammatory markers, including tumor necrosis factor-α (TNFα) and C-reactive protein (CRP). Local adipose tissue inflammation and circulating concentrations of TNFα and CRP were negatively associated with SI, and circulating concentrations of TNFα and CRP were also negatively associated with skeletal muscle oxidative capacity. These results demonstrate that obese humans exhibit increased adipose tissue inflammation concurrently with increased systemic inflammation, reduced insulin sensitivity, and reduced muscle oxidative capacity and suggest that adipose tissue and systemic inflammation may drive obesity-associated metabolic derangements.NEW AND NOTEWORTHY Adipose inflammation is proposed to be at the nexus of the systemic inflammation and metabolic derangements associated with obesity. The present study provides evidence to support adipose inflammation as a central feature of the pathophysiology of obesity. Adipose inflammation is associated with systemic and peripheral metabolic derangements, including increased systemic inflammation, reduced insulin sensitivity, and reduced skeletal muscle mitochondrial respiration.

The effect of dietary nitrate on exercise capacity in chronic kidney disease: a randomized controlled pilot study

BackgroundChronic Kidney Disease (CKD) patients exhibit a reduced exercise capacity that impacts quality of life. Dietary nitrate supplementation has been shown to have favorable effects on exercise capacity in disease populations by reducing the oxygen cost of exercise. This study investigated whether dietary nitrates would acutely improve exercise capacity in CKD patients. Methods and resultsIn this randomized, double-blinded crossover study, 12 Stage 3–4 CKD patients (Mean ± SEM: Age, 60 ± 5yrs; eGFR, 50.3 ± 4.6 ml/min/1.73 m2) received an acute dose of 12.6 mmol of dietary nitrate in the form of concentrated beetroot juice (BRJ) and a nitrate depleted placebo (PLA). Skeletal muscle mitochondrial oxidative function was assessed using near-infrared spectroscopy. Cardiopulmonary exercise testing was performed on a cycle ergometer, with intensity increased by 25 W every 3 min until volitional fatigue. Plasma nitric oxide (NO) metabolites (NOm; nitrate, nitrite, low molecular weight S-nitrosothiols, and metal bound NO) were determined by gas-phase chemiluminescence. Plasma NOm values were significantly increased following BRJ (BRJ vs. PLA: 1074.4 ± 120.4 μM vs. 28.4 ± 6.6 μM, p < 0.001). Total work performed (44.4 ± 10.6 vs 39.6 ± 9.9 kJ, p = 0.03) and total exercise time (674 ± 85 vs 627 ± 86s, p = 0.04) were significantly greater following BRJ. Oxygen consumption at the ventilatory threshold was also improved by BRJ (0.90 ± 0.08 vs. 0.74 ± 0.06 L/min, p = 0.04). These changes occurred in the absence of improved skeletal muscle mitochondrial oxidative capacity (p = 0.52) and VO2peak (p = 0.35). ConclusionsOur findings demonstrate that inorganic nitrate can acutely improve exercise capacity in CKD patients. The effects of chronic nitrate supplementation on CKD related exercise intolerance should be investigated in future studies.

Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty.

BACKGROUNDPhysical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies; however, their presence or link to EI in the frail older adult is unknown.METHODSHere, we studied 3 groups of ambulatory, community-dwelling adults with no history of significant coronary disease: frail older (FO) individuals (81 ± 2.7 years, mean ± SEM), nonfrail older (NFO) individuals (79 ± 2.0 years), and healthy middle-aged individuals, who served as controls (CONT, 51 ± 2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with 31P magnetic resonance (MR) techniques during graded multistage plantar flexion exercise (PFE). EI was quantified by a 6-minute walk (6MW) and peak oxygen consumption during cardiopulmonary testing (peak VO2).RESULTSDuring graded exercise, FO, NFO, and CONT individuals all fatigued at similar SM HEP levels, as measured by 31P-MR. However, FO individuals fatigued fastest, with several-fold higher rates of PFE-induced HEP decline that correlated closely with shorter exercise duration in the MR scanner and with 6MW distance and lower peak oxygen consumption on cardiopulmonary testing (P < 0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI.CONCLUSIONSeveral-fold faster SM energetic decline during exercise occurs in FO individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations.FUNDINGThis work was supported by NIH R21 AG045634, R01 AG063661, R01 HL61912, the Johns Hopkins University Claude D. Pepper Older Americans Independence Center P30AG021334, and the Clarence Doodeman Endowment in Cardiology at Johns Hopkins.

Association between muscle aerobic capacity and whole-body peak oxygen uptake.

Decline in skeletal muscle mitochondrial oxidative capacity (MOC) is associated with reduced aerobic capacity and increased risk ofcardiovascular and metabolicdisease. Measuring skeletal muscle MOC may be an alternative method to assess aerobic capacity, especiallyfor individuals unable to perform a whole-body maximum oxygen uptake protocol. In this study, linear regression analysis in two leg muscles was performed to determine whether MOC values could be used to predict whole-body peak oxygen uptake. MOC was measured with near infrared spectroscopy (NIRS) inthemedial gastrocnemius (MG) and vastus lateralis (VL) musclesof 26 participants (age, 27.1 ± 5.8years old). Whole-body peak oxygen uptake (VO2 peak) was determinedby indirect calorimetry during a continuous ramp protocol on a cycle ergometer. VO2 peak values were significantly correlated with the muscle recovery rate constant (k)ofthe MG (kMG,r = 0.59;p < 0.01) and VL (kVL,r = 0.63; p < 0.01) muscles. Summingrecovery rate constantsof both muscles together (kMG + kVL)improved thestrength of thecorrelation with VO2 peak (r = 0.78;p < 0.0001)andcouldexplain amajorityof the variance(R2 = 0.61)between the two measurements. Data suggest that NIRS can provide reliable MOC measurements on two leg muscles that correlate well with whole-body peak oxygen uptake.

Skeletal Muscle Oxidative Capacity is Linked to Cardiovascular Health

BackgroundCardiovascular disease (CVD) affects 48% of the adult population and is the leading cause of death in the United States. Vascular stiffness, endothelial dysfunction, and decreased skeletal muscle health are each independently associated with increased CVD risk. This study sought to test the hypothesis that indices of vascular health are associated with skeletal muscle function in the general population.Methods22 (16 women and 6 men) apparently healthy adults participated in this study. Dual energy x‐ray absorptiometry was performed to obtain body composition and skeletal muscle mass. Carotid‐femoral pulse wave velocity (PWVCF), augmentation index normalized for heart rate (AI@75bpm), and flow mediated dilation normalized for shear rate (FMD/Shear) were assessed to evaluate arterial stiffness and endothelial function. Handgrip strength was assessed using a handgrip dynamometer and skeletal muscle mitochondrial oxidative capacity (Kox cap) was assessed using near‐infrared spectroscopy (NIRS) to evaluate indices of skeletal muscle health and function, respectively.ResultsKox cap was inversely correlated with both carotid‐femoral pulse wave velocity PWVCF (r= −0.515; p= 0.014) and AI@75BPM (r= −0.453; p= 0.034). In addition, a trend in the relationship between FMD/Shear and Kox cap (r= 0.326; p= 0.139) was observed. Compared with women, men had significantly higher PWVCF (p= 0.008), handgrip strength (p&lt; 0.001), and skeletal muscle mass (p= 0.006); however, muscle function was similar (p= 0.209) between sexes.ConclusionsThese findings demonstrate that improved muscle function can favorably impact vascular health. Additionally, skeletal muscle strength and size were significantly different between sexes; however, muscle function was similar. These data highlight the importance of assessing all three indices of muscle health. Future studies are warranted to investigate if increases in vascular endothelial function will improve skeletal muscle function and contribute to prevention of CVD.Support or Funding InformationThis project was supported in part by The Augusta University Medical Scholars Program (AB) and NIH R01DK117365 (RAH and XW).

Serum Acylglyceride Metabolites are Negatively Associated with Muscle Oxidative Capacity, but Not with Physical Activity, in Severe COPD

RATIONALEChronic obstructive pulmonary disease (COPD) is associated with altered metabolism and body composition that accompany worse outcomes. Serum lipid metabolites are dysregulated in COPD (e.g. sphingolipids, polyunsaturated fatty acids, ceramides). Loss of skeletal muscle mitochondrial oxidative capacity is implicated in mediating the association between hyperlipidemia and COPD. As both oxidative capacity and physical activity are negatively associated with COPD severity, this study aimed to determine whether lipid dysregulation in COPD was associated with muscle oxidative capacity and/or physical inactivity. We hypothesized that alteration of lipid metabolites in COPD would be associated with muscle oxidative capacity, independent of pulmonary function.METHODSCurrent and former smokers with COPD (n=44, FEV1=61±4%pred) and without COPD (CON) (n=63, FEV1=93±2%pred) volunteered. Untargeted prime and lipid metabolites were measured using liquid chromatography and mass spectrometry. Medial gastrocnemius oxidative capacity was assessed at rest from the recovery rate constant (k) of muscle oxygen consumption using near‐infrared spectroscopy. Daily step count and physical activity (average vector magnitude units (VMU)/min) were measured over 7 days by waist‐worn triaxial accelerometer.RESULTSThe k value (1.12±0.05 vs. 1.68±0.06 min−1, P&lt;0.0001) and VMU/min (170±26 vs. 450±50 VMU/min, P=0.004) were lower in severe COPD (FEV1&lt;50%pred, n=14–16) compared with CON. 129 prime metabolites and 470 lipids with known identity were quantified. Using sex as a covariate, lipidomics revealed that 24 lipids (19 sphingomeylins) were differentially expressed in COPD, consequent to a diminished sex difference of sphingomeylins in COPD (FDR&lt;0.05). Total, and some individual, fatty acid concentrations were greater in severe COPD than in CON (FDR&lt;0.05). After adjusting for FEV1%pred, we observed that grouped diacylglyceride (DG; Spearman’s rho = −0.745, FDR=0.03) and triacylglyceride (TG; rho = −0.811, FDR=0.01) were negatively associated with muscle oxidative capacity, but not physical activity, in severe COPD.DISCUSSIONWe found 24 lipids, including 19 sphingomyelins, increased in COPD with sex as covariant; and that sex‐dependent differences in sphingomyelin in CON were diminished COPD. This may contribute to more rapid progression of COPD in women than in men. Strong negative associations between blood lipids and muscle oxidative capacity, but not physical activity, suggest that impaired mitochondrial function may play a role in the accumulation of serum aclyglycerides in severe COPD. These data provide a strong rationale for targeting mitochondrial deficits by exercise training, or other means, to improve outcomes in COPD.Support or Funding InformationShenzhen Technology University (RL); VA MERT I01 BX00435, R01HL111437, R01HL129727 (TKH); Swiss National Science Foundation P300P3_151705 (AA); ATS‐2014‐03, Pulmonary Education and Research Foundation (HBR); R01HL089856; R01HL089897; UL1TR000124.

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

BackgroundAfrican 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/DesignA 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).DiscussionThe 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 registrationClinicalTrials.gov identifier: NCT02892331. Registered on September 8, 2016.

Low plasma lysophosphatidylcholines are associated with impaired mitochondrial oxidative capacity in adults in the Baltimore Longitudinal Study of Aging.

The decrease in skeletal muscle mitochondrial oxidative capacity with age adversely affects muscle strength and physical performance. Factors that are associated with this decrease have not been well characterized. Low plasma lysophosphatidylcholines (LPC), a major class of systemic bioactive lipids, are predictive of aging phenotypes such as cognitive impairment and decline of gait speed in older adults. Therefore, we tested the hypothesis that low plasma LPC are associated with impaired skeletal muscle mitochondrial oxidative capacity. Skeletal muscle mitochondrial oxidative capacity was measured using in vivo phosphorus magnetic resonance spectroscopy (31P‐MRS) in 385 participants (256 women, 129 men), aged 24–97 years (mean 72.5) in the Baltimore Longitudinal Study of Aging. Postexercise recovery rate of phosphocreatine (PCr), k PCr, was used as a biomarker of mitochondrial oxidative capacity. Plasma LPC were measured using liquid chromatography–tandem mass spectrometry. Adults in the highest quartile of k PCr had higher plasma LPC 16:0 (p = 0.04), 16:1 (p = 0.004), 17:0 (p = 0.01), 18:1 (p = 0.0002), 18:2 (p = 0.002), and 20:3 (p = 0.0007), but not 18:0 (p = 0.07), 20:4 (p = 0.09) compared with those in the lower three quartiles in multivariable linear regression models adjusting for age, sex, and height. Multiple machine‐learning algorithms showed an area under the receiver operating characteristic curve of 0.638 (95% confidence interval, 0.554, 0.723) comparing six LPC in adults in the lower three quartiles of k PCr with the highest quartile. Low plasma LPC are associated with impaired mitochondrial oxidative capacity in adults.

Protein malnutrition mitigates the effects of a high-fat diet on glucose homeostasis in mice.

Nutrient malnutrition, during the early stages of development, may facilitate the onset of metabolic diseases later in life. However, the consequences of nutritional insults, such as a high-fat diet(HFD) after protein restriction, are still controversial. We assessed overall glucose homeostasis and molecular markers of mitochondrial function in the gastrocnemius muscle of protein-restricted mice fed an HFD until early adulthood. Male C57BL/6 mice were fed a control (14% protein-control diet) or a protein-restricted (6% protein-restricted diet) diet for 6 weeks. Afterward, mice received an HFD or not for 8 weeks (mice fed a control diet and HFD [CH] and mice fed a protein-restricted diet and HFD [RH]). RH mice showed lower weight gain and fat accumulation and did not show an increase in fasting plasma glucose and insulin levels compared with CH mice. RH mice showed higher energy expenditure, increased citrate synthase, peroxisome-proliferator-activated receptor gamma coactivator 1-alpha protein content, and higher levels of malate and α-ketoglutarate compared with CH mice. Moreover, RH mice showed increased AMPc-dependent kinase and acetyl coenzyme-A (CoA) carboxylase phosphorylation, lower intramuscular triacylglycerol content, and similar malonyl-CoA levels. In conclusion, protein undernourishment after weaning does not potentiate fat accumulation and insulin resistance in adult young mice fed an HFD. This outcome seems to be associated with increased skeletal muscle mitochondrial oxidative capacity and reduced lipids accumulation.