Acute responsiveness to single leg cycling in adults with obesity.

Obesity is associated with several skeletal muscle impairments which can be improved through an aerobic exercise prescription. The possibility that exercise responsiveness is diminished in people with obesity has been suggested but not well-studied. The purpose of this study was to investigate how obesity influences acute exercise responsiveness in skeletal muscle and circulating amino metabolites. Non-obese (NO; n = 19; 10F/9M; BMI = 25.1 ± 2.8 kg/m2 ) and Obese (O; n = 21; 14F/7M; BMI = 37.3 ± 4.6 kg/m2 ) adults performed 30 min of single-leg cycling at 70% of VO2 peak. 13 C6 -Phenylalanine was administered intravenously for muscle protein synthesis measurements. Serial muscle biopsies (vastus lateralis) were collected before exercise and 3.5- and 6.5-h post-exercise to measure protein synthesis and gene expression. Targeted plasma metabolomics was used to quantitate amino metabolites before and 30 and 90 min after exercise. The exercise-induced fold change in mixed muscle protein synthesis trended (p = 0.058) higher in NO (1.28 ± 0.54-fold) compared to O (0.95 ± 0.42-fold) and was inversely related to BMI (R2  = 0.140, p = 0.027). RNA sequencing revealed 331 and 280 genes that were differentially expressed after exercise in NO and O, respectively. Gene set enrichment analysis showed O had six blunted pathways related to metabolism, cell to cell communication, and protein turnover after exercise. The circulating amine response further highlighted dysregulations related to protein synthesis and metabolism in adults with obesity at the basal state and in response to the exercise bout. Collectively, these data highlight several unique pathways in individuals with obesity that resulted in a modestly blunted exercise response.

Impaired hemodynamic response to exercise in patients with peripheral artery disease: evidence of a link to inflammation and oxidative stress.

An exaggerated mean arterial blood pressure (MAP) response to exercise in patients with peripheral artery disease (PAD), likely driven by inflammation and oxidative stress and, perhaps, required to achieve an adequate blood flow response, is well described. However, the blood flow response to exercise in patients with PAD actually remains equivocal. Therefore, eight patients with PAD and eight healthy controls completed 3 min of plantar flexion exercise at both an absolute work rate (WR) (2.7 W, to evaluate blood flow) and a relative intensity (40%WRmax, to evaluate MAP). The exercise-induced change in popliteal artery blood flow (BF, Ultrasound Doppler), MAP (Finapress), and vascular conductance (VC) were quantified. In addition, resting markers of inflammation and oxidative stress were measured in plasma and muscle biopsies. Exercise-induced ΔBF, assessed at 2.7 W, was lower in PAD compared with controls (PAD: 251 ± 150 vs. Controls: 545 ± 187 mL/min, P < 0.001), whereas ΔMAP, assessed at 40%WRmax, was greater for PAD (PAD: 23 ± 14 vs. Controls: 11 ± 6 mmHg, P = 0.028). The exercise-induced ΔVC was lower for PAD during both the absolute WR (PAD: 1.9 ± 1.6 vs. Controls: 4.7 ± 1.9 mL/min/mmHg) and relative intensity exercise (PAD: 1.9 ± 1.8 vs. Controls: 5.0 ± 2.2 mL/min/mmHg) trials (both, P < 0.01). Inflammatory and oxidative stress markers, including plasma interleukin-6 and muscle protein carbonyls, were elevated in PAD (both, P < 0.05), and significantly correlated with the hemodynamic changes during exercise (r = -0.57 to -0.78, P < 0.05). Thus, despite an exaggerated ΔMAP response, patients with PAD exhibit an impaired exercise-induced ΔBF and ΔVC, and both inflammation and oxidative stress likely play a role in this attenuated hemodynamic response.

Impact of obesity on the molecular response to a single bout of exercise in a preliminary human cohort.

OBJECTIVE: The health benefits of exercise are well documented, but several exercise-response parameters are attenuated in individuals with obesity. The goal of this pilot study was to identify molecular mechanisms that may influence exercise response with obesity. METHODS: A multi-omics comparison of the transcriptome, proteome, and phosphoproteome in muscle from a preliminary cohort of lean individuals (n = 4) and individuals with obesity (n = 4) was performed, before and after a single bout of 30 minutes of unilateral cycling at 70% maximal oxygen uptake (VO2 peak). Mass spectrometry and RNA sequencing were used to interrogate the proteome, phosphoproteome, and transcriptome from muscle biopsy tissue. RESULTS: The main findings are that individuals with obesity exhibited transcriptional and proteomic signatures consistent with reduced mitochondrial function, protein synthesis, and glycogen synthesis. Furthermore, individuals with obesity demonstrated markedly different transcriptional, proteomic, and phosphoproteomic responses to exercise, particularly biosynthetic pathways of glycogen synthesis and protein synthesis. Casein kinase II subunit alpha and glycogen synthase kinase-3ß signaling was identified as exercise-response pathways that were notably altered by obesity. CONCLUSIONS: Opportunities to enhance exercise responsiveness by targeting specific molecular pathways that are disrupted in skeletal muscle from individuals with obesity await a better understanding of the precise molecular mechanisms that may limit exercise-response pathways in obesity.

Dealing with a Pandemic: Emerging Tools, Solutions, and Challenges.

As a result of the COVID-19 pandemic, nations across the globe have responded by attempting to understand how the virus was spreading in their communities, in order to isolate cases, reduce morbidity and mortality, and avoid overwhelming healthcare facilities. In this article, we describe the global response to tracking the virus and discuss new technological advances in molecular testing that have been deployed and developed to track and mitigate COVID-19. We also discuss how the successes and failures observed in the COVID-19 pandemic can be extrapolated to improve our ability to respond to the next pandemic.

Skeletal muscle mitochondrial dysfunction and muscle and whole body functional deficits in cancer patients with weight loss.

Reductions in skeletal muscle mass and function are often reported in patients with cancer-associated weight loss and are associated with reduced quality of life, impaired treatment tolerance, and increased mortality. Although cellular changes, including altered mitochondrial function, have been reported in animals, such changes have been incompletely characterized in humans with cancer. Whole body and skeletal muscle physical function, skeletal muscle mitochondrial function, and whole body protein turnover were assessed in eight patients with cancer-associated weight loss (10.1 ± 4.2% body weight over 6-12 mo) and 19 age-, sex-, and body mass index (BMI)-matched healthy controls to characterize skeletal muscle changes at the whole body, muscle, and cellular level. Potential pathways involved in cancer-induced alterations in metabolism and mitochondrial function were explored by interrogating skeletal muscle and plasma metabolomes. Despite similar lean mass compared with control participants, patients with cancer exhibited reduced habitual physical activity (57% fewer daily steps), cardiorespiratory fitness [22% lower V̇o2peak (mL/kg/min)] and leg strength (35% lower isokinetic knee extensor strength), and greater leg neuromuscular fatigue (36% greater decline in knee extensor torque). Concomitant with these functional declines, patients with cancer had lower mitochondrial oxidative capacity [25% lower State 3 O2 flux (pmol/s/mg tissue)] and ATP production [23% lower State 3 ATP production (pmol/s/mg tissue)] and alterations in phospholipid metabolite profiles indicative of mitochondrial abnormalities. Whole body protein turnover was unchanged. These findings demonstrate mitochondrial abnormalities concomitant with whole body and skeletal muscle functional derangements associated with human cancer, supporting future work studying the role of mitochondria in the muscle deficits associated with cancer.NEW & NOTEWORTHY To our knowledge, this is the first study to suggest that skeletal muscle mitochondrial deficits are associated with cancer-associated weight loss in humans. Mitochondrial deficits were concurrent with reductions in whole body and skeletal muscle functional capacity. Whether mitochondrial deficits are causal or secondary to cancer-associated weight loss and functional deficits remains to be determined, but this study supports further exploration of mitochondria as a driver of cancer-associated losses in muscle mass and function.

COVID-19 Seroprevalence and Active Infection in an Asymptomatic Population.

In response to the COVID-19 pandemic, immediate and scalable testing solutions are needed to direct return to full capacity planning in the general public and across the Department of Defense (DoD). To fully understand the extent to which a population has been affected by COVID-19, active monitoring approaches require an estimation of overall seroprevalence in addition to accurate, affordable, and rapid tests to detect current SARS-CoV-2 infection. In this study, researchers in the Air Force Research Laboratory's 711th Human Performance Wing, Airman Systems Directorate evaluated the performance of various testing methods for the detection of SARS-CoV-2 antibodies and viral RNA in asymptomatic adults working at Wright-Patterson Air Force Base and the surrounding area during the period of 23 July 2020-23 Oct 2020. Altogether, there was a seroprevalance of 3.09% and an active infection rate of 0.5% (determined via the testing of saliva samples) amongst individuals tested, both of which were comparable to local and national averages at the time. This work also presents technical and non-technical assessments of various testing strategies as compared to the gold standard approaches (e.g., lateral flow assays vs. ELISA and RT-LAMP vs. RT-PCR) in order to explore orthogonal supply chains and fieldability. Exploration and validation of multiple testing strategies will allow the DoD and other workforces to make informed responses to COVID-19 and future pandemics.

Acute high-intensity exercise and skeletal muscle mitochondrial respiratory function: role of metabolic perturbation.

Recently it was documented that fatiguing, high-intensity exercise resulted in a significant attenuation in maximal skeletal muscle mitochondrial respiratory capacity, potentially due to the intramuscular metabolic perturbation elicited by such intense exercise. With the utilization of intrathecal fentanyl to attenuate afferent feedback from group III/IV muscle afferents, permitting increased muscle activation and greater intramuscular metabolic disturbance, this study aimed to better elucidate the role of metabolic perturbation on mitochondrial respiratory function. Eight young, healthy males performed high-intensity cycle exercise in control (CTRL) and fentanyl-treated (FENT) conditions. Liquid chromatography-mass spectrometry and high-resolution respirometry were used to assess metabolites and mitochondrial respiratory function, respectively, pre- and postexercise in muscle biopsies from the vastus lateralis. Compared with CTRL, FENT yielded a significantly greater exercise-induced metabolic perturbation (PCr: -67% vs. -82%, Pi: 353% vs. 534%, pH: -0.22 vs. -0.31, lactate: 820% vs. 1,160%). Somewhat surprisingly, despite this greater metabolic perturbation in FENT compared with CTRL, with the only exception of respiratory control ratio (RCR) (-3% and -36%) for which the impact of FENT was significantly greater, the degree of attenuated mitochondrial respiratory capacity postexercise was not different between CTRL and FENT, respectively, as assessed by maximal respiratory flux through complex I (-15% and -33%), complex II (-36% and -23%), complex I + II (-31% and -20%), and state 3CI+CII control ratio (-24% and -39%). Although a basement effect cannot be ruled out, this failure of an augmented metabolic perturbation to extensively further attenuate mitochondrial function questions the direct role of high-intensity exercise-induced metabolite accumulation in this postexercise response.

Preserved skeletal muscle oxidative capacity in older adults despite decreased cardiorespiratory fitness with ageing.

KEY POINTS: Healthy older adults exhibit lower cardiorespiratory fitness ( V̇O2peak ) than young in the absence of any age-related difference in skeletal muscle mitochondrial capacity, suggesting central haemodynamics plays a larger role in age-related declines in V̇O2peak . Total physical activity did not differ by age, but moderate-to-vigorous physical activity was lower in older compared to young adults. Moderate-to-vigorous physical activity is associated with V̇O2peak and muscle oxidative capacity, but physical inactivity cannot entirely explain the age-related reduction in V̇O2peak . ABSTRACT: Declining fitness ( V̇O2peak ) is a hallmark of ageing and believed to arise from decreased oxygen delivery and reduced muscle oxidative capacity. Physical activity is a modifiable lifestyle factor that is critical when evaluating the effects of age on parameters of fitness and energy metabolism. The objective was to evaluate the effects of age and sex on V̇O2peak , muscle mitochondrial physiology, and physical activity in young and older adults. An additional objective was to assess the contribution of skeletal muscle oxidative capacity to age-related reductions in V̇O2peak and determine if age-related variation in V̇O2peak and muscle oxidative capacity could be explained on the basis of physical activity levels. In 23 young and 52 older men and women measurements were made of V̇O2peak , mitochondrial physiology in permeabilized muscle fibres, and free-living physical activity by accelerometry. Regression analyses were used to evaluate associations between age and V̇O2peak , mitochondrial function, and physical activity. Significant age-related reductions were observed for V̇O2peak (P < 0.001), but not muscle mitochondrial capacity. Total daily step counts did not decrease with age, but older adults showed lower moderate-to-vigorous physical activity, which was associated with V̇O2peak (R2  = 0.323, P < 0.001) and muscle oxidative capacity (R2  = 0.086, P = 0.011). After adjusting for sex and physical activity, age was negatively associated with V̇O2peak but not muscle oxidative capacity. Healthy older adults exhibit lower V̇O2peak but preserved mitochondrial capacity compared to young. Physical activity, particularly moderate-to-vigorous, is a key factor in observed age-related changes in fitness and muscle oxidative capacity, but cannot entirely explain the age-related reduction in V̇O2peak .

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 ß 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.

Science and Technology Solutions for Scalable SARS-CoV-2 Testing to Inform Return to Full Capacity Strategy in United States Air Force Workforce Personnel.

SARS-CoV-2 has highlighted the requirement for a drastic change in pandemic response. While cases continue to rise, there is an urgent need to deploy sensitive and rapid testing in order to identify potential outbreaks before there is an opportunity for further community spread. Currently, reverse transcription quantitative polymerase chain reaction (RT-qPCR) is considered the gold standard for diagnosing an active infection, using a nasopharyngeal swab; however, it can take days after symptoms develop to properly identify and trace the infection. While many civilian jobs can be performed remotely, the Department of Defense (DOD) is by nature a very fluid organization which requires in-person interaction and a physical presence to maintain effectiveness. In this commentary, we examine several current and emergent technologies and their ability to identify both active and previous SARS-CoV-2 infection, possibly in those without symptoms. Further, we will explore an ongoing study at the Air Force Research Laboratory, utilizing Reverse Transcription Loop-mediated isothermal amplification (RT-LAMP), next-generation sequencing, and the presence of SARS-CoV-2 antibodies through Lateral Flow Immunoassays. The ability to identify SARS-CoV-2 through volatile organic compound biomarker identification will also be explored. By exploring and validating multiple testing strategies, and contributing to Operation Warp Speed, the DOD is postured to respond to SARS-CoV-2, and future pandemics.

Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism.

The immune system plays a multifunctional role throughout the regenerative process, regulating both pro-/anti-inflammatory phases and progenitor cell function. In the present study, we identify the myokine/cytokine Meteorin-like (Metrnl) as a critical regulator of muscle regeneration. Mice genetically lacking Metrnl have impaired muscle regeneration associated with a reduction in immune cell infiltration and an inability to transition towards an anti-inflammatory phenotype. Isochronic parabiosis, joining wild-type and whole-body Metrnl knock-out (KO) mice, returns Metrnl expression in the injured muscle and improves muscle repair, providing supportive evidence for Metrnl secretion from infiltrating immune cells. Macrophage-specific Metrnl KO mice are also deficient in muscle repair. During muscle regeneration, Metrnl works, in part, through Stat3 activation in macrophages, resulting in differentiation to an anti-inflammatory phenotype. With regard to myogenesis, Metrnl induces macrophage-dependent insulin-like growth factor 1 production, which has a direct effect on primary muscle satellite cell proliferation. Perturbations in this pathway inhibit efficacy of Metrnl in the regenerative process. Together, these studies identify Metrnl as an important regulator of muscle regeneration and a potential therapeutic target to enhance tissue repair.

Author Correction: Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Passive leg movement in chronic obstructive pulmonary disease: evidence of locomotor muscle vascular dysfunction.

Chronic obstructive pulmonary disease (COPD), characterized by pulmonary dysfunction, is now also recognized to be associated with free radical-mediated vascular dysfunction. However, as previous investigations have utilized the brachial artery flow-mediated dilation technique, whether such vascular dysfunction exists in the locomotor muscle of patients with COPD remains unclear. Therefore, in patients with COPD (n = 13, 66 ± 6 yr) and healthy age- and sex-matched control subjects (n = 12, 68 ± 6 yr), second-by-second measurements of leg blood flow (LBF) (ultrasound Doppler), mean arterial pressure (MAP) (Finapres), and leg vascular conductance (LVC) were recorded before and during both 2 min of continuous upright seated continuous-movement passive leg movement (PLM) and a single-movement PLM (sPLM). In response to PLM, both peak change in LBF (COPD 321 ± 54, Control 470 ± 55 ∆mL/min) and LVC (COPD 3.0 ± 0.5, Control 5.4 ± 0.5 ∆mL·min-1·mmHg-1) were significantly attenuated in patients with COPD compared with control subjects (P < 0.05). This attenuation in the patients with COPD was also evident in response to sPLM, with peak change in LBF tending to be lower (COPD 142 ± 26, Control 169 ± 14 ∆mL/min) and LVC being significantly lower (P < 0.05) in the patients than the control subjects (COPD 1.6 ± 0.4, Control 2.5 ± 0.3 ∆mL·min-1·mmHg-1). Therefore, utilizing both PLM and sPLM, this study provides evidence of locomotor muscle vascular dysfunction in patients with COPD, perhaps due to redox imbalance and reduced nitric oxide bioavailability, which is in agreement with an increased cardiovascular disease risk in this population. This locomotor muscle vascular dysfunction, in combination with the clearly dysfunctional lungs, may contribute to the exercise intolerance associated with COPD.NEW & NOTEWORTHY Utilizing both the single and continuous passive leg movement (PLM) models, which induce nitric oxide (NO)-dependent hyperemia, this study provides evidence of vascular dysfunction in the locomotor muscle of patients with chronic obstructive pulmonary disease (COPD), independent of central hemodynamics. This impaired hyperemia may be the result of an oxidant-mediated attenuation in NO bioavailability. In addition to clearly dysfunctional lungs, vascular dysfunction in locomotor muscle may contribute to the exercise intolerance associated with COPD and increased cardiovascular disease risk.

Metabo- and mechanoreceptor expression in human heart failure: Relationships with the locomotor muscle afferent influence on exercise responses.

NEW FINDINGS: What is the central question of this study? How do locomotor muscle metabo- and mechanoreceptor expression compare in heart failure patients and controls? Do relationships exist between the protein expression and cardiopulmonary responses during exercise with locomotor muscle neural afferent feedback inhibition? What is the main finding and its importance? Heart failure patients exhibited greater protein expression of transient receptor potential vanilloid type 1 and cyclooxygenase-2 than controls. These findings are important as they identify receptors that may underlie the augmented locomotor muscle neural afferent feedback in heart failure. ABSTRACT: Heart failure patients with reduced ejection fraction (HFrEF) exhibit abnormal locomotor group III/IV afferent feedback during exercise; however, the underlying mechanisms are unclear. Therefore, the purpose of this study was to determine (1) metabo- and mechanoreceptor expression in HFrEF and controls and (2) relationships between receptor expression and changes in cardiopulmonary responses with afferent inhibition. Ten controls and six HFrEF performed 5 min of cycling exercise at 65% peak workload with lumbar intrathecal fentanyl (FENT) or placebo (PLA). Arterial blood pressure and catecholamines were measured via radial artery catheter. A vastus lateralis muscle biopsy was performed to quantify cyclooxygenase-2 (COX-2), purinergic 2X3 (P2X3 ), transient receptor potential vanilloid type 1 (TRPV 1), acid-sensing ion channel 3 (ASIC3 ), Piezo 1 and Piezo 2 protein expression. TRPV 1 and COX-2 protein expression was greater in HFrEF than controls (both P < 0.04), while P2X3 , ASIC3 , and Piezo 1 and 2 were not different between groups (all P > 0.16). In all participants, COX-2 protein expression was related to the percentage change in ventilation (r = -0.66) and mean arterial pressure (MAP) (r = -0.82) (both P < 0.01) with FENT (relative to PLA) during exercise. In controls, TRPV 1 protein expression was related to the percentage change in systolic blood pressure (r = -0.77, P = 0.02) and MAP (r = -0.72, P = 0.03) with FENT (relative to PLA) during exercise. TRPV 1 and COX-2 protein levels are elevated in HFrEF compared to controls. These findings suggest that the elevated TRPV 1 and COX-2 expression may contribute to the exaggerated locomotor muscle afferent feedback during cycling exercise in HFrEF.

Attenuated activation of the unfolded protein response following exercise in skeletal muscle of older adults.

Sarcopenia is linked with impaired adaptive responses to exercise in aging skeletal muscle. The unfolded protein response (UPR) is an important intramyocellular molecular response pathway that is activated by exercise. The influence of age on skeletal muscle adaptive UPR in response to exercise, and the relationship to other key exercise-responsive regulatory pathways is not well-understood. We evaluated age-related changes in transcriptional markers of UPR activation following a single bout of resistance exercise in 12 young (27 ± 5yrs) and 12 older (75 ± 5yrs) healthy men and women. At baseline, there were modest differences in expression of UPR-related genes in young and older adults. Following exercise, transcriptional markers of UPR pathway activation were attenuated in older adults compared to young based on specific salient UPR-related genes and gene set enrichment analysis. The coordination of post-exercise transcriptional patterns between the UPR pathway, p53/p21 axis of autophagy, and satellite cell differentiation were less evident in older compared to young adults. In conclusion, transcriptomic analysis revealed an age-related decline in the adaptive UPR transcriptional response following a single bout of exercise that could contribute to impaired exercise responsiveness with age.

Acute High-Intensity Exercise Impairs Skeletal Muscle Respiratory Capacity.

PURPOSE: The effect of an acute bout of exercise, especially high-intensity exercise, on the function of mitochondrial respiratory complexes is not well understood, with potential implications for both the healthy population and patients undergoing exercise-based rehabilitation. Therefore, this study sought to comprehensively examine respiratory flux through the different complexes of the electron transport chain in skeletal muscle mitochondria before and immediately after high-intensity aerobic exercise. METHODS: Muscle biopsies of the vastus lateralis were obtained at baseline and immediately after a 5-km time trial performed on a cycle ergometer. Mitochondrial respiratory flux through the complexes of the electron transport chain was measured in permeabilized skeletal muscle fibers by high-resolution respirometry. RESULTS: Complex I + II state 3 (state 3CI + CII) respiration, a measure of oxidative phosphorylation capacity, was diminished immediately after the exercise (pre, 27 ± 3 ρm·mg·s; post, 17 ± 2 ρm·mg·s; P < 0.05). This decreased oxidative phosphorylation capacity was predominantly the consequence of attenuated complex II-driven state 3 (state 3CII) respiration (pre, 17 ± 1 ρm·mg·s; post, 9 ± 2 ρm·mg·s; P < 0.05). Although complex I-driven state 3 (3CI) respiration was also lower (pre, 20 ± 2 ρm·mg·s; post, 14 ± 4 ρm·mg·s), this did not reach statistical significance (P = 0.27). In contrast, citrate synthase activity, proton leak (state 2 respiration), and complex IV capacity were not significantly altered immediately after the exercise. CONCLUSIONS: These findings reveal that acute high-intensity aerobic exercise significantly inhibits skeletal muscle state 3CII and oxidative phosphorylation capacity. This, likely transient, mitochondrial defect might amplify the exercise-induced development of fatigue and play an important role in initiating exercise-induced mitochondrial adaptations.

Oxygen availability and skeletal muscle oxidative capacity in patients with peripheral artery disease: implications from in vivo and in vitro assessments.

Evidence suggests that the peak skeletal muscle mitochondrial ATP synthesis rate ( Vmax) in patients with peripheral artery disease (PAD) may be attenuated due to disease-related impairments in O2 supply. However, in vitro assessments suggest intrinsic deficits in mitochondrial respiration despite ample O2 availability. To address this conundrum, Doppler ultrasound, near-infrared spectroscopy, phosphorus magnetic resonance spectroscopy, and high-resolution respirometry were combined to assess convective O2 delivery, tissue oxygenation, Vmax, and skeletal muscle mitochondrial capacity (complex I + II, state 3 respiration), respectively, in the gastrocnemius muscle of 10 patients with early stage PAD and 11 physical activity-matched healthy control (HC) subjects. All participants were studied in free-flow control conditions (FF) and with reactive hyperemia (RH) induced by a period of brief ischemia during the last 30 s of submaximal plantar flexion exercise. Patients with PAD repeated the FF and RH trials under hyperoxic conditions (FF + 100% O2 and RH + 100% O2). Compared with HC subjects, patients with PAD exhibited attenuated O2 delivery at the same absolute work rate and attenuated tissue reoxygenation and Vmax after relative intensity-matched exercise. Compared with the FF condition, only RH + 100% O2 significantly increased convective O2 delivery (~44%), tissue reoxygenation (~54%), and Vmax (~60%) in patients with PAD ( P < 0.05), such that Vmax was now not different from HC subjects. Furthermore, there was no evidence of an intrinsic mitochondrial deficit in PAD, as assessed in vitro with adequate O2. Thus, in combination, this comprehensive in vivo and in vitro investigation implicates O2 supply as the predominant factor limiting mitochondrial oxidative capacity in early stage PAD. NEW & NOTEWORTHY Currently, there is little accord as to the role of O2 availability and mitochondrial function in the skeletal muscle dysfunction associated with peripheral artery disease. This is the first study to comprehensively use both in vivo and in vitro approaches to document that the skeletal muscle dysfunction associated with early stage peripheral artery disease is predominantly a consequence of limited O2 supply and not the impact of an intrinsic mitochondrial defect in this pathology.

Increased skeletal muscle mitochondrial free radical production in peripheral arterial disease despite preserved mitochondrial respiratory capacity.

NEW FINDINGS: What is the central question of this study? What is the degree to which skeletal muscle mitochondria-derived reactive oxygen species (ROS) production is linked to impaired skeletal muscle function in patients with early-stage peripheral arterial disease (PAD) and what is the impact on mitochondrial respiratory capacity? What is the main finding and its importance? This is the first study to document increased mitochondria-derived reactive oxygen species production associated with elevated intramuscular oxidative stress, despite preserved mitochondrial respiratory function, in patients with PAD. Furthermore, systemic inflammation, mitochondria-derived ROS production and skeletal muscle oxidative stress were strongly correlated to disease severity, as indicated by ankle-brachial index, in patients with PAD. ABSTRACT: Skeletal muscle mitochondrial dysfunction, which is not fully explained by disease-related arterial occlusion, has been implicated in the pathophysiology of peripheral arterial disease (PAD). Therefore, this study comprehensively assessed mitochondrial respiratory function in biopsies from the gastrocnemius of 10 patients with PAD (Fontaine Stage II) and 12 healthy controls (HC). Intramuscular and systemic inflammation, mitochondria-derived reactive oxygen species (ROS) production, and oxidative stress were also assessed to better understand the mechanisms responsible for the proposed PAD-induced mitochondrial dysfunction. Interestingly, mitochondrial respiratory capacity, assessed as complex I (CI) and complex II (CII)-driven State 3 respiration, measured separately and in combination (State 3 CI+II), revealed no difference between the patients with PAD and the HC. However, mitochondria-derived ROS production was significantly elevated in PAD (HC: 1.0 ± 0.9; PAD: 4.3 ± 1.0 AU (mg tissue)-1 ). Furthermore, patients with PAD exhibited significantly greater concentrations of the pro-inflammatory markers tumour necrosis factor α in plasma (HC: 0.9 ± 0.4; PAD: 2.0 ± 0.3 pg ml-1 ) and interleukin 6 in both plasma (HC: 2.3 ± 0.4; PAD: 4.3 ± 0.5 pg ml-1 ) and muscle (∼75% greater). Intramuscular oxidative stress, assessed by protein carbonyls and 4-hydroxynonenal, was significantly greater in PAD compared to HC. Ankle brachial index was significantly correlated with intramuscular inflammation, oxidative stress and mitochondria-derived ROS production. Thus, elevated intramuscular inflammation, oxidative stress and mitochondria-derived ROS production are likely to contribute to the pathophysiology of the skeletal muscle dysfunction associated with PAD, even in the presence of preserved mitochondrial respiratory function in this population.

Impaired Muscle Efficiency but Preserved Peripheral Hemodynamics and Mitochondrial Function With Advancing Age: Evidence From Exercise in the Young, Old, and Oldest-Old.

Muscle weakness in the elderly has been linked to recurrent falls and morbidity; therefore, elucidating the mechanisms contributing to the loss of muscle function and mobility with advancing age is critical. To this aim, we comprehensively examined skeletal muscle metabolic function and hemodynamics in 11 young (23 ± 2 years), 11 old (68 ± 2 years), and 10 oldest-old (84 ± 2 years) physical activity-matched participants. Specifically, oxidative stress markers, mitochondrial function, and the ATP cost of contraction as well as peripheral hemodynamics were assessed during dynamic plantar flexion exercise at 40 per cent of maximal work rate (WRmax). Both the PCr recovery time constant and the peak rate of mitochondrial ATP synthesis were not significantly different between groups. In contrast, the ATP cost of dynamic contractions (young: 1.5 ± 1.0, old: 3.4 ± 2.1, oldest-old: 6.1 ± 3.6 mM min-1 W-1) and systemic markers of oxidative stress were signficantly increased with age, with the ATP cost of contraction being negatively correlated with WRmax (r = .59, p < .05). End-of-exercise blood flow per Watt rose significantly with increasing age (young: 37 ± 20, old: 82 ± 68, oldest-old: 154 ± 93 mL min-1 W-1). These findings suggest that the progressive deterioration of muscle contractile efficiency with advancing age may play an important role in the decline in skeletal muscle functional capacity in the elderly.