Muscle Mitochondrial Function Research Articles

Activation of innate immunity selectively compromises mitochondrial complex I, proline oxidation, and flight activity in the major arbovirus vector Aedes aegypti.

Aedes aegypti females are natural vectors of important arboviruses such as dengue, zika, and yellow fever. Mosquitoes activate innate immune response signaling pathways upon infection, as a resistance mechanism to fight pathogens and limit their propagation. Despite the beneficial effects of immune activation for insect vectors, phenotypic costs ultimately affect their fitness. However, the underlying mechanisms that mediate these fitness costs remain poorly understood. Given the high energy required to mount a proper immune response, we hypothesized that systemic activation of innate immunity would impair flight muscle mitochondrial function, compromising tissue energy demand and flight activity. Here, we investigated the dynamic effects of activation of innate immunity by intra-thoracic zymosan injection on A. aegypti flight muscle mitochondrial metabolism. Zymosan injection significantly increased defensin A expression in fat bodies in a time-dependent manner that compromised flight activity. Although oxidant levels in flight muscle were hardly altered, ATP-linked respiratory rates driven by mitochondrial pyruvate+proline oxidation were significantly reduced at 24 h upon zymosan injection. Oxidative phosphorylation coupling was preserved regardless of innate immune response activation along 24 h. Importantly, rotenone-sensitive respiration and complex I-III activity were specifically reduced 24 h upon zymosan injection. Also, loss of complex I activity compromised ATP-linked and maximal respiratory rates mediated by mitochondrial proline oxidation. Finally, the magnitude of innate immune response activation negatively correlated with respiratory rates, regardless of the metabolic states. Collectively, we demonstrate that activation of innate immunity is strongly associated with reduced flight muscle complex I activity with direct consequences to mitochondrial proline oxidation and flight activity. Remarkably, our results indicate a trade-off between dispersal and immunity exists in an insect vector, underscoring the potential consequences of disrupted flight muscle mitochondrial energy metabolism to arbovirus transmission.

104 Effects of providing vitamin and mineral supplementation throughout gestation on subsequent F1 replacement heifer liver and muscle oxygen consumption and mitochondrial function throughout pregnancy

Abstract The study aimed to assess the impact of maternal vitamin/mineral supplementation during gestation on the energy utilization in liver and muscle tissues of F1 heifer offspring. We hypothesized that VTM supplementation during gestation would mitigate mitochondrial energy loss and uncoupling of liver and muscle tissue in pregnant offspring. At breeding, crossbred Angus heifers [n = 31; initial body weight (BW) = 412.5 ± 53.68 kg] were randomly assigned to either a basal diet targeting BW gains of 0.45 kg•heifer-1•d-1(CON; n = 14) or the basal diet plus 113 g•heifer-1•d-1of a vitamin/mineral supplement (VTM; n = 17). Heifers remained on their respective dietary treatments until calving. After calving, all F1 heifer calves were raised in a single management group with their dams until weaning (BW = 209 ± 4.82 kg; VTM, n = 17; CON, n = 12) and fed a common diet throughout postnatal development. At breeding and throughout gestation, F1 heifers (n = 9, VTM; n = 7, CON) were allotted daily feed intakes of 1.5% of BW on a dry-matter basis as a total mixed ration and used to evaluate cellular energy metabolism throughout pregnancy. Liver and Longissimus dorsi muscle biopsies were collected on d 179 and d 247 +/- 3 of gestation and mitochondrial function was assessed via high resolution respirometry (Oroboros Instruments, Innsbruck, Austria). The following respiratory states were evaluated: LEAK respiration (L), OXPHOS capacity (P), NADH-linked OXPHOS (PI), and electron transfer capacity (E). Data were analyzed using the MIXED procedure of SAS with repeated measures where appropriate. No treatment × trimester interaction (P ≥ 0.13) was observed for any of the respiratory states in liver and muscle. Hepatic oxygen consumption was not influenced by maternal gestational VTM supplementation (P ≥ 0.68), or stage of gestation (P ≥ 0.27). In muscle, L respiration was the only state affected by maternal dietary treatments, being greater (P = 0.05) in CON than VTM heifers. Additionally, L respiration was greater (P = 0.02) during the third trimester compared with the second trimester. This observation in CON heifers is important because increased L respiration (proton leak) results in decreased ATP production. Protons that escape the intermembrane space, are dissipated as heat rather than be used for ATP synthesis; thus, oxygen consumption increases to compensate for the reduction of protons entering ATP turnover. Results show increased muscle mitochondria inefficiency in offspring with dams lacking supplementation during pregnancy. The increased incidence of proton leak results in potentially less efficient cattle as protons escape the electron transport chain rather than be transformed for energy utilization need of the animal, thus VTM supplementation throughout pregnancy impacts fetal development with potential effects in live offspring 18 to 22 mo post-parturition.

Myokine Secretion following an Aerobic Exercise Intervention in Individuals with Type 2 Diabetes with or without Exercise Resistance.

Type 2 diabetes (T2D) is characterized by muscle metabolic dysfunction that exercise can minimize, but some patients do not respond to an exercise intervention. Myokine secretion is intrinsically altered in patients with T2D, but the role of myokines in exercise resistance in this patient population has never been studied. We sought to determine if changes in myokine secretion were linked to the response to an exercise intervention in patients with T2D. The participants followed a 10-week aerobic exercise training intervention, and patients with T2D were grouped based on muscle mitochondrial function improvement (responders versus non-responders). We measured myokines in serum and cell-culture medium of myotubes derived from participants pre- and post-intervention and in response to an in vitro model of muscle contraction. We also quantified the expression of genes related to inflammation in the myotubes pre- and post-intervention. No significant differences were detected depending on T2D status or response to exercise in the biological markers measured, with the exception of modest differences in expression patterns for certain myokines (IL-1β, IL-8, IL-10, and IL-15). Further investigation into the molecular mechanisms involving myokines may explain exercise resistance with T2D; however, the role in metabolic adaptations to exercise in T2D requires further investigation.

Migration increases mitochondrial oxidative capacity without increasing reactive oxygen species emission in a songbird.

Birds remodel their flight muscle metabolism prior to migration to meet the physiological demands of migratory flight, including increases in both oxidative capacity and defence against reactive oxygen species. The degree of plasticity mediated by changes in these mitochondrial properties is poorly understood but may be explained by two non-mutually exclusive hypotheses: variation in mitochondrial quantity or individual mitochondrial function. We tested these hypotheses using yellow-rumped warblers (Setophaga coronata), a Nearctic songbird which biannually migrates two to five thousand kilometres. We predicted higher flight muscle mitochondrial abundance and substrate oxidative capacity and decreased reactive oxygen species emission in migratory warblers captured during autumn migration compared to a short-day photoperiod-induced non-migratory phenotype. We assessed mitochondrial abundance via citrate synthase activity and assessed isolated mitochondrial function using high-resolution fluororespirometry. We found 60% higher tissue citrate synthase activity in the migratory phenotype, indicating higher mitochondrial abundance. We also found 70% higher state 3 respiration (expressed per unit citrate synthase) in mitochondria from migratory warblers when oxidizing palmitoyl-carnitine, but similar H2O2 emission rates between phenotypes. By contrast, non-phosphorylating respiration was higher and H2O2 emission rates were lower in the migratory phenotype. However, flux through electron transport system complexes I-IV, II-IV and IV were similar between phenotypes. In support of our hypotheses, these data suggest that flight muscle mitochondrial abundance and function are seasonally remodeled in migratory songbirds to increase tissue oxidative capacity without increasing reactive oxygen species formation.

Local and systemic responses to repeated gluteal muscle microbiopsies in mature sedentary horses

We aimed to test the hypothesis that repeated muscle collections would impact mitochondrial function, antioxidant status, and markers of inflammation and muscle damage. Twenty-six horses (8 geldings, 18 mares; mean ± SD 9.5 ± 3.5 y) had gluteus medius muscle biopsy samples collected at: 0 and 24h (n=7); 0 and 6h (n = 6); 0, 6, and 12h (n=7); or 0, 6, 12, and 24h (n=6). Blood was collected from all horses every 6h for 72h, starting 24h prior to the 0h muscle collection. Data were analyzed using mixed linear models. Muscle integrative (per mg tissue) electron transfer capacity of complex II decreased (P=0.004) and intrinsic (relative to citrate synthase (CS) activity) LEAK increased (P<0.03) from 0 to 6h but both returned to 0h levels by 12h. Activity of CS was greater at 0 than 12 and 24h (P≤0.02). Serum creatine kinase (CK) activity was similar from -24 through 0h but increased in all horses at 6h and remained elevated through 48h (P<0.05) though not above reference ranges. Whole blood superoxide dismutase activity fluctuated throughout the 72-h collection period (P=0.03) and serum cortisol concentration displayed a circadian pattern (P<0.0001) but neither were altered by muscle collections. No other variable, including muscle mitochondrial capacities and function, blood and muscle antioxidant status and concentrations of select cytokines, and serum amyloid A, differed by time or muscle collection. Repeated gluteal collections had limited short-term or no effect on physiological markers in unstressed, mature horses except serum CK activity, which should be interpreted with caution during repeated tissue collections.

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.

Reduced exercise capacity occurs before intrinsic skeletal muscle dysfunction in experimental rat models of pulmonary hypertension.

Reduced exercise capacity in pulmonary hypertension (PH) significantly impacts quality of life. However, the cause of reduced exercise capacity in PH remains unclear. The objective of this study was to investigate whether intrinsic skeletal muscle changes are causative in reduced exercise capacity in PH using preclinical PH rat models with different PH severity. PH was induced in adult Sprague-Dawley (SD) or Fischer (CDF) rats with one dose of SU5416 (20 mg/kg) injection, followed by 3 weeks of hypoxia and additional 0-4 weeks of normoxia exposure. Control s rats were injected with vehicle and housed in normoxia. Echocardiography was performed to assess cardiac function. Exercise capacity was assessed by VO2 max. Skeletal muscle structural changes (atrophy, fiber type switching, and capillary density), mitochondrial function, isometric force, and fatigue profile were assessed. In SD rats, right ventricular systolic dysfunction is associated with reduced exercise capacity in PH rats at 7-weektimepoint in comparison to control rats, while no changes were observed in skeletal muscle structure, mitochondrial function, isometric force, or fatigue profile. CDF rats at 4-weektimepoint developed a more severe PH and, in addition to right ventricular dysfunction, the reduced exercise capacity in these rats is associated with skeletal muscle atrophy; however, mitochondrial function, isometric force, and fatigue profile in skeletal muscle remain unchanged. Our data suggest that cardiopulmonary impairments in PH are the primary cause of reduced exercise capacity, which occurs before intrinsic skeletal muscle dysfunction.

Plasma metabolomic markers underlying skeletal muscle mitochondrial function relationships with cognition and motor function.

Lower skeletal muscle mitochondrial function is associated with future cognitive impairment and mobility decline, but the biological underpinnings for these associations are unclear. We examined metabolomic markers underlying skeletal muscle mitochondrial function, cognition and motor function. We analysed data from 560 participants from the Baltimore Longitudinal Study of Aging (mean age: 68.4years, 56% women, 28% Black) who had data on skeletal muscle oxidative capacity (post-exercise recovery rate of phosphocreatine, kPCr) via 31P magnetic resonance spectroscopy and targeted plasma metabolomics using LASSO model. We then examined which kPCr-related markers were also associated with cognition and motor function in a larger sample (n = 918, mean age: 69.4, 55% women, 27% Black). The LASSO model revealed 24 metabolites significantly predicting kPCr, with the top 5 being asymmetric dimethylarginine, lactic acid, lysophosphatidylcholine a C18:1, indoleacetic acid and triacylglyceride (17:1_34:3), also significant in multivariable linear regression. The kPCr metabolite score was associated with cognitive or motor function, with 2.5-minute usual gait speed showing the strongest association (r = 0.182). Five lipids (lysophosphatidylcholine a C18:1, phosphatidylcholine ae C42:3, cholesteryl ester 18:1, sphingomyelin C26:0, octadecenoic acid) and 2 amino acids (leucine, cystine) were associated with both cognitive and motor function measures. Our findings add evidence to the hypothesis that mitochondrial function is implicated in the pathogenesis of cognitive and physical decline with aging and suggest that targeting specific metabolites may prevent cognitive and mobility decline through their effects on mitochondria. Future omics studies are warranted to confirm these findings and explore mechanisms underlying mitochondrial dysfunction in aging phenotypes.

Effects of manipulating Kingfish (Seriola lalandi) routine oxygen demand and supply on ventricular and skeletal muscle mitochondrial function

SummaryYellowtail kingfish (Seriola lalandi) are a highly active marine species, with increasing value in commercial aquaculture. While practices which manipulate oxygen (O2) dynamics through metabolic demand and environmental O2 supply have been shown to impact juvenile growth rate in fish development, there has been no work exploring the effects of O2 at the subcellular level. In addition, manipulation of O2 supply or demand via changes in environmental factors such as O2 levels or salinity, may impact whole animal performance. Still, there has been little work exploring the physiological effects at a subcellular level. Mitochondria (mt) consume O2 and are pivotal in central metabolism, directly impacting growth, and dictating whole animal performance. Here we explore the effects of manipulating O2 demand and supply on mt in yellowtail kingfish ventricle and skeletal muscle by exposure to chronic hyperoxia (200% [O2], 35 ppt) and to hypoosmotic conditions (100% [O2], 17.5 ppt). Chronic exposure to hypoosmotic conditions resulted in greater overall biomass, while it lowered relative ventricular mass compared to control fish. Mitochondrial respiratory flux for most measures remained consistent with control fish, with the exception of cytochrome c oxidase (COX) respiration. Chronic hyperoxia had no impact on overall morphology, and no significant effect on ventricle mt respiration, yet increased COX activity in skeletal muscle. These data indicate that lowering routine mt O2 demands in S. lalandi with hypoosmotic conditions has more impact than increasing O2 availability, and that this may enhance biomass output while maintaining mt integrity.

Association between dietary phosphate intake and skeletal muscle energetics in adults without cardiovascular disease.

Highly bioavailable inorganic phosphate (Pi) is present in large quantities in the typical Western diet and represents a large fraction of total phosphate intake. Dietary Pi excess induces exercise intolerance and skeletal muscle mitochondrial dysfunction in normal mice. However, the relevance of this to humans remains unknown. The study was conducted on 13 individuals without a history of cardiopulmonary disease (46% female, 15% Black participants) enrolled in the pilot-phase of the Dallas Heart and Mind Study. Total dietary phosphate was estimated from 24-h dietary recall (ASA24). Muscle ATP synthesis was measured at rest, and phosphocreatinine (PCr) dynamics was measured during plantar flexion exercise using 7-T 31P magnetic resonance (MR) spectroscopy in the calf muscle. Correlation was assessed between dietary phosphate intake normalized to total caloric intake, resting ATP synthesis, and PCr depletion during exercise. Higher dietary phosphate intake was associated with lower resting ATP synthesis (r = -0.62, P = 0.03), and with higher levels of PCr depletion during plantar flexion exercise relative to the resting period (r = -0.72; P = 0.004). These associations remain significant after adjustment for age and estimated glomerular filtration rate (both P < 0.05). High dietary phosphate intake was also associated with lower serum Klotho levels, and Klotho levels are in turn associated with PCr depletion and higher ADP accumulation post exercise. Our study suggests that higher dietary phosphate is associated with reduced skeletal muscle mitochondrial function at rest and exercise in humans providing new insight into potential mechanisms linking the Western diet to impaired energy metabolism.NEW & NOTEWORTHY This is the first translational research study directly demonstrating the adverse effects of dietary phosphate on muscle energy metabolism in humans. Importantly, our data show that dietary phosphate is associated with impaired muscle ATP synthesis at rest and during exercise, independent of age and renal function. This is a new biologic paradigm with significant clinical dietary implications.

Childhood adverse life events and skeletal muscle mitochondrial function.

Social stress experienced in childhood is associated with adverse health later in life. Mitochondrial function has been implicated as a mechanism for how stressful life events "get under the skin" to influence physical well-being. Using data from the Study of Muscle, Mobility, and Aging (n = 879, 59% women), linear models examined whether adverse childhood events (i.e., physical abuse) were associated with two measures of skeletal muscle mitochondrial energetics in older adults: (i) maximal adenosine triphosphate production (ATPmax) and (ii) maximal state 3 respiration (Max OXPHOS). Forty-five percent of the sample reported experiencing one or more adverse childhood events. After adjustment, each additional event was associated with -0.08 SD (95% confidence interval = -0.13, -0.02) lower ATPmax. No association was observed with Max OXPHOS. Adverse childhood events are associated with lower ATP production in later life. Findings indicate that mitochondrial function may be a mechanism for understanding how early social stress influences health in later life.

A study protocol to investigate if acipimox improves muscle function and sarcopenia: an open-label, uncontrolled, before-and-after experimental medicine feasibility study in community-dwelling older adults

IntroductionSarcopenia is the age-associated loss of muscle mass and strength. Nicotinamide adenine dinucleotide (NAD) plays a central role in both mitochondrial function and cellular ageing processes implicated in sarcopenia. NAD...

Exercise Training Differentially Affects Skeletal Muscle Mitochondria in Rats with Inherited High or Low Exercise Capacity.

Exercise capacity has been related to morbidity and mortality. It consists of an inherited and an acquired part and is dependent on mitochondrial function. We assessed skeletal muscle mitochondrial function in rats with divergent inherited exercise capacity and analyzed the effect of exercise training. Female high (HCR)- and low (LCR)-capacity runners were trained with individually adapted high-intensity intervals or kept sedentary. Interfibrillar (IFM) and subsarcolemmal (SSM) mitochondria from gastrocnemius muscle were isolated and functionally assessed (age: 15 weeks). Sedentary HCR presented with higher exercise capacity than LCR paralleled by higher citrate synthase activity and IFM respiratory capacity in skeletal muscle of HCR. Exercise training increased exercise capacity in both HCR and LCR, but this was more pronounced in LCR. In addition, exercise increased skeletal muscle mitochondrial mass more in LCR. Instead, maximal respiratory capacity was increased following exercise in HCRs' IFM only. The results suggest that differences in skeletal muscle mitochondrial subpopulations are mainly inherited. Exercise training resulted in different mitochondrial adaptations and in higher trainability of LCR. HCR primarily increased skeletal muscle mitochondrial quality while LCR increased mitochondrial quantity in response to exercise training, suggesting that inherited aerobic exercise capacity differentially affects the mitochondrial response to exercise training.

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.

HDL-C and apolipoprotein A-I are independently associated with skeletal muscle mitochondrial function in healthy humans.

Prior animal and cell studies have demonstrated a direct role of high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-I) in enhancing skeletal muscle mitochondrial function and exercise capacity. However, the relevance of these animal and cell investigations in humans remains unknown. Therefore, a cross-sectional study was conducted in 48 adults (67% female, 8% Black participants, age 39 ± 15.4 yr old) to characterize the associations between HDL measures, ApoA-I, and muscle mitochondrial function. Forearm muscle oxygen recovery time (tau) from postexercise recovery kinetics was used to assess skeletal muscle mitochondrial function. Lipoprotein measures were assessed by nuclear magnetic resonance. HDL efflux capacity was assessed using J774 macrophages, radiolabeled cholesterol, and apolipoprotein B-depleted plasma both with and without added cyclic adenosine monophosphate. In univariate analyses, faster skeletal muscle oxygen recovery time (lower tau) was significantly associated with higher levels of HDL cholesterol (HDL-C), ApoA-I, and larger mean HDL size, but not HDL cholesterol efflux capacity. Slower recovery time (higher tau) was positively associated with body mass index (BMI) and fasting plasma glucose (FPG). In multivariable linear regression analyses, higher levels of HDL-C and ApoA-I, as well as larger HDL size, were independently associated with faster skeletal muscle oxygen recovery times that persisted after adjusting for BMI and FPG (all P < 0.05). In conclusion, higher levels of HDL-C, ApoA-I, and larger mean HDL size were independently associated with enhanced skeletal muscle mitochondrial function in healthy humans.NEW & NOTEWORTHY Our study provides the first direct evidence supporting the beneficial role of HDL-C and ApoA-I on enhanced skeletal muscle mitochondrial function in healthy young to middle-aged humans without cardiometabolic disease.

Chronic aryl hydrocarbon receptor activity impairs muscle mitochondrial function with tobacco smoking.

Accumulating evidence has demonstrated that chronic tobacco smoking directly contributes to skeletal muscle dysfunction independent of its pathological impact to the cardiorespiratory systems. The mechanisms underlying tobacco smoke toxicity in skeletal muscle are not fully resolved. In this study, the role of the aryl hydrocarbon receptor (AHR), a transcription factor known to be activated with tobacco smoke, was investigated. AHR related gene (mRNA) expression was quantified in skeletal muscle from adult controls and patients with chronic obstructive pulmonary disease (COPD), as well as mice with and without cigarette smoke exposure. Utilizing both skeletal muscle-specific AHR knockout mice exposed to chronic repeated (5days per week for 16weeks) cigarette smoke and skeletal muscle-specific expression of a constitutively active mutant AHR in healthy mice, a battery of assessments interrogating muscle size, contractile function, mitochondrial energetics, and RNA sequencing were employed. Skeletal muscle from COPD patients (N=79, age=67.0±8.4years) had higher levels of AHR (P=0.0451) and CYP1B1 (P<0.0001) compared to healthy adult controls (N=16, age=66.5±6.5years). Mice exposed to cigarette smoke displayed higher expression of Ahr (P=0.008), Cyp1b1 (P<0.0001), and Cyp1a1 (P<0.0001) in skeletal muscle compared to air controls. Cigarette smoke exposure was found to impair skeletal muscle mitochondrial oxidative phosphorylation by ~50% in littermate controls (Treatment effect, P<0.001), which was attenuated by deletion of the AHR in muscle in male (P=0.001), but not female, mice (P=0.37), indicating there are sex-dependent pathological effects of smoking-induced AHR activation in skeletal muscle. Viral mediated expression of a constitutively active mutant AHR in the muscle of healthy mice recapitulated the effects of cigarette smoking by decreasing muscle mitochondrial oxidative phosphorylation by ~40% (P=0.003). These findings provide evidence linking chronic AHR activation secondary to cigarette smoke exposure to skeletal muscle bioenergetic deficits in male, but not female, mice. AHR activation is a likely contributor to the decline in muscle oxidative capacity observed in smokers and AHR antagonism may provide a therapeutic avenue aimed to improve muscle function in COPD.

Cardiovascular and muscular plasticity in an endurance-master athlete following 12 weeks of detraining and retraining: A case study.

Introduction&#x0D; This study aimed at examining the cardiorespiratory and muscular adaptations following 12 weeks of detraining and retraining in a 53-year-old endurance master athlete.&#x0D; Methods&#x0D; Data were collected before and after detraining and after retraining. Maximal oxygen uptake (VO2max) was evaluated during maximal cycling exercise. Proteins involved in muscle contraction, mitochondrial function and glycolysis were investigated using western blot analysis.&#x0D; Results&#x0D; VO2max decreased by 7% after detraining and was 5% greater than baseline after retraining. Detraining induced an important increase in the ryanodine receptor type 1 protein levels (RyR1, +44%) with a decrease in the protein levels of its stabilizer FKBP12 (-24%). We observed a 138% increase in the sarco-endoplasmic reticulum ATPase 1 protein and a 42% increase in the myosin heavy chain fast-twitch protein in response to detraining, suggesting transformation towards a more glycolytic phenotype. This was associated with depressed levels of the mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) proteins, while the expression of the mitochondrial dynamic proteins appeared stimulated. Twelve weeks of retraining reversed almost all the alterations observed in muscle proteins, but specifically increased mitochondrial biogenesis, OXPHOS and antioxidant defense proteins as well as the glucose transporter 4 (Glut -4, +36%) and hexokinase (+100%) proteins levels compared to baseline. The mitochondrial dynamic proteins were further increased with the retraining.&#x0D; Discussion/Conclusion&#x0D; These data provide novel information on cardiorespiratory and muscular plasticity suggesting that highly endurance-trained athletes might show substantial muscular adaptations while retrained after a detraining period and call for more extensive clinical trials.

Passive exercise is an effective alternative to HRT for restoring OVX induced mitochondrial dysfunction in skeletal muscle.

Postmenopausal women are more prone to develop muscle weakness, which is strongly associated with impairment of mitochondrial function in skeletal muscle. This study aimed to examine the impact of a passive exercise modality, whole-body vibration training (WBVT), on muscle mitochondrial function in ovariectomized (OVX) mice, in comparison with 17β-estradiol (E2) replacement. Female C57BL/6J mice were assigned to four groups: sham operation control group (Sham), ovariectomized group (OVX), OVX with E2 supplement group (OVX+E), and OVX with WBVT group (OVX+W). The estrous cycle, body weight, body composition, and muscle strength of the mice were monitored after the operation. Serum E2 level was assessed by enzyme-linked immunosorbent assay (ELISA). The ATP levels were determined using a luciferase-catalyzed bioluminescence assay. The activity of mitochondrial respiration chain complexes was evaluated using high-resolution respirometry (O2K). Expression levels of oxidative phosphorylation (OXPHOS), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and mitochondrial transcription factor A (TFAM) were detected using western blotting. We observed decreased muscle strength and impaired mitochondrial function in the skeletal muscle of OVX mice. The vibration training alleviated these impairments as much as the E2 supplement. In addition, the vibration training was superior to the ovariectomy and the estradiol replacement regarding the protein expression of PGC-1α and TFAM. WBVT improves the OVX-induced decline in muscle strength and impairment of mitochondrial function in the skeletal muscle. This passive exercise strategy may be useful as an alternative to E2 replacement for preventing menopausal muscular weakness. Further studies are needed to understand the effects of WBVT on various physiological systems, and precautions should be taken when implementing it in patient treatment.

Dietary Ferulic Acid Increases Endurance Capacity by Promoting Skeletal Muscle Oxidative Phenotype, Mitochondrial Function, and Antioxidant Capacity.

Endurance capacity is essential for endurance athletes' achievement and individuals' health. Nutritional supplements are a proven way to enhance endurance capacity. Previous studies have shown that ferulic acid (FA) enhances endurance capacity, but the underlying mechanism is unclear. The study is aimed to investigate the mechanism by which FA increases endurance capacity. Forty mice are divided into control and 0.5% FA-supplemented groups, and an exhaustive swimming test demonstrates increased endurance capacity with FA supplementation. This study investigates the underlying mechanism for this effect of FA. Firstly, RT-PCR and western blot analysis find that FA increases the transformation from fast to slow muscle fiber. Additionally, adenosine triphosphate concentration, metabolic enzyme activity, and mitochondrial DNA analysis find that FA increases mitochondrial biogenesis and activates nuclear factor erythroid 2-related factor (NRF)1 signaling pathway in muscle. Besides, through antioxidant capacity analysis, this study finds that FA activates NRF2 signaling pathway and improves the antioxidant capacity in muscle. Moreover, inhibiting NRF2 eliminates FA's effect on muscle fiber transformation in C2C12 cells. Our results suggest that FA increases endurance capacity by promoting skeletal muscle oxidative phenotype, mitochondrial function, and antioxidant capacity, which may be related to the NRF1 and NRF2 signaling pathways.

Cannabinoids improve mitochondrial function in skeletal muscle of exhaustive exercise training rats by inhibiting mitophagy through the PINK1/PARKIN and BNIP3 pathways

Cannabidiol (CBD) is a pure natural phytocannabinoid derived from cannabis that has anti-inflammatory, antiapoptotic and antioxidative stress abilities. In recent years, an increasing number of studies have reported the regulatory effect of CBD on skeletal muscle injury induced by exercise, but its mechanism is still unclear. Mitochondria are the main organelles responsible for the energy supply within eukaryotic cells, and their function has been closely linked to cellular health. Moderate exercise improves mitochondrial function, but the excessive exercise has a negative impact on mitochondria. Therefore, we speculate that CBD may promote exercise induced skeletal muscle cell damage by improving mitochondrial function. In this study, by establishing an animal model of exhaustive exercise training in rats, the protective effect of CBD on skeletal muscle mitochondrial structure and function was elaborated, and the possible molecular mechanism was discussed based on transcriptomics. Our results indicate that skeletal muscle mitochondrial structure and function were improved after CBD intervention. GO and KEGG pathway enrichment analysis showed that exhaustive exercise training induced mitochondrial dysfunction in skeletal muscle is associated with excessive autophagy/mitophagy, the signaling pathways involved in FOXO3 and GABARAPL1 may play important roles. After CBD intervention, the protein expression of PINK1, PARKIN and BNIP3 was down-regulated, indicating that CBD may improve the mitochondrial function by inhibiting mitophagy through the PINK1/PARKIN and BNIP3 pathway.