Exercise Training-induced Adaptations Research Articles

Metabolic mitochondrial alterations prevail in the female rat heart 8 weeks after exercise cessation.

The consumption of high-caloric diets strongly contributes to the development of non-communicable diseases (NCDs), including cardiovascular disease, the leading cause of mortality worldwide. Exercise (along with diet intervention) is one of the primary non-pharmacological approaches to promote a healthier lifestyle and counteract the rampant prevalence of NCDs. The present study evaluated the effects of exercise cessation after a short period training on the cardiac metabolic and mitochondrial function of female rats. Seven-week-old female Sprague-Dawley rats were fed a control or a high-fat, high-sugar (HFHS) diet and, after 7 weeks, the animals were kept on a sedentary lifestyle or submitted to endurance exercise for 3 weeks (6 days per week, 20-60 min/day). The cardiac samples were analysed 8 weeks after exercise cessation. The consumption of the HFHS diet triggered impaired glucose tolerance, whereas the HFHS diet and physical exercise resulted in different responses in plasma adiponectin and leptin levels. Cardiac mitochondrial respiration efficiency was decreased by the HFHS diet consumption, which led to reduced ATP and increased NAD(P)H mitochondrial levels, which remained prevented by exercise 8 weeks after cessation. Exercise training-induced cardiac adaptations in redox balance, namely increased relative expression of Nrf2 and downstream antioxidant enzymes persist after an eight-week exercise cessation period. Endurance exercise modulated cardiac redox balance and mitochondrial efficiency in female rats fed a HFHS diet. These findings suggest that exercise may elicit cardiac adaptations crucial for its role as a non-pharmacological intervention for individuals at risk of developing NCDs.

Inflammation- and Tissue Remodeling-Related Gene Responses in Skeletal Muscle of Heart Failure Patients Following High-Intensity Interval Training.

Peripheral myopathy consists a hallmark of heart failure (HF) and has been associated with poor prognosis. Inflammation has been suggested to dominate this pathology, while exercise training is typically associated with the induction of anti-inflammatory mechanisms. However, the current knowledge regarding the involvement of inflammation-related genes in the exercise training-induced muscle adaptations in HF patients is very limited. Given that high-intensity interval training (HIIT) alone or combined with strength training (COM) has gained ground in HF cardiac rehabilitation, this study aimed to investigate the local muscle expression of inflammatory and tissue remodeling factors in HF patients, who underwent 3 months of these training schemes. In addition, we examined whether these exercise training-induced gene expression responses are associated with changes in exercise capacity in those patients. Thirteen male patients with chronic HF (age: 51 13 y; body mass index (BMI): 27 4 kg/ ) were randomly assigned to a 3-month exercise program consisted of either HIIT (N = 6) or COM training (N = 7). Muscle tissue biopsies were obtained from vastus lateralis pre- and post-training and transcriptional changes in interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-1 alpha (TNF-1 ), urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), and transforming growth factor-beta 1 (TGF- 1) were quantified by RT-PCR. An overall increase in the expression levels of selected inflammatory (IL-8, TNF-1 ) and remodeling factors (uPAR) was found post-training (p 0.05), while IL-6, uPA and TGF- 1 gene expression remained unchanged (p 0.05). The observed alterations did not differ between training groups. Additionally, IL-8 changes were found to be correlated with the improvement in exercise capacity post-training (p 0.05). This is the first study demonstrating an increase in intramuscular inflammatory and remodeling key factors induced by HIIT or COM training in HF patients. Combining these observations with our previous findings of improved muscle hypertrophy and capillarization post-training in these patients, the findings of the present study may suggest that inflammatory responses are part of an ongoing remodeling process in the exercising skeletal muscle. NCT02387411.

Microvascular Function in Skeletal Muscle of Adiponectin Knockout Mice

Adiponectin is known to be an important regulator of both metabolic and vascular function in skeletal muscle; however, a direct role for adiponectin in exercise training‐induced microvascular adaptation of skeletal muscle has not been documented. We assessed oxidative metabolism, capillarity, and endothelium‐dependent vasodilation in soleus and gastrocnemius muscles of sedentary and exercise trained, wild type (WT) and adiponectin knockout (AdipoKO) mice. WT and AdipoKO mice were obtained at 10‐12 wks of age and underwent treadmill exercise training (1 hr/day, 5 days/wk for 8 wks) or remained sedentary in cages. In sedentary mice, citrate synthase activity and capillarity were increased in soleus muscle of AdiopKO mice as compared to WT mice. In soleus muscle feed arteries from sedentary mice, endothelium‐dependent vasodilation to acetylcholine was reduced in AdipoKO mice as compared to WT mice. Exercise training increased capillarity and citrate synthase activity in soleus muscle of WT mice, but not AdipoKO mice. Exercise training did not alter endothelium‐dependent dilation in soleus feed arteries from either AdipoKO or WT mice. In 1A arterioles from the gastrocnemius muscle of sedentary mice, endothelium‐dependent vasodilation to acetylcholine was not altered in AdipoKO compared to WT mice; however, exercise training increased endothelium‐dependent vasodilation to acetylcholine in WT, but not AdipoKO mice. These data suggest that deletion of adiponectin and a reduction of endothelial vasodilatory function stimulates a compensatory increase in oxidative capacity and capillarity in soleus muscle; however, no further increase in these parameters occurs in soleus muscle of AdipoKO mice in response to exercise training. In contrast, in gastrocnemius muscle, endothelial vasodilatory function was not affected by deletion of adiponectin in sedentary mice, but endothelium‐dependent vasodilation of 1A arterioles increased in response to exercise training in WT, but not in AdipoKO mice. Taken together, these data suggest that the role of adiponectin in adaptation of metabolic and microvascular function in response to exercise training is muscle‐specific.

The effect of fibroblast growth factor receptor inhibition on resistance exercise training-induced adaptation of bone and muscle quality in mice.

Aging in mammals, including humans, is accompanied by loss of bone and muscular function and mass, characterized by osteoporosis and sarcopenia. Although resistance exercise training (RET) is considered an effective intervention, its effect is blunted in some elderly individuals. Fibroblast growth factor (FGF) and its receptor, FGFR, can modulate bone and muscle quality during aging and physical performance. To elucidate this possibility, the FGFR inhibitor NVP-BGJ398 was administrated to C57BL/6n mice for 8 weeks with or without RET. Treatment with NVP-BGJ398 decreased grip strength, muscular endurance, running capacity and bone quality in the mice. FGFR inhibition elevated bone resorption and relevant gene expression, indicating altered bone formation and resorption. RET attenuated tibial bone resorption, accompanied by changes in the expression of relevant genes. However, RET did not overcome the detrimental effect of NVP-BGJ398 on muscular function. Taken together, these findings provide evidence that FGFR signaling may have a potential role in the maintenance of physical performance and quality of bone and muscles.

Exercise training-induced adaptations in lung cancer patients who have undergone a lobectomy.

To determine the safety and effectiveness of a prescribed, individualized, 12-week exercise intervention on cardiorespiratory function, muscular strength, and quality of life in lung cancer patients who have undergone a lobectomy. In addition, we sought to compare the exercise training response of lung cancer patients who have undergone a lobectomy to a population of cancer patients with all other cancers in order to examine the specific effects of a lobectomy when compared to cancer patients at large. Participants were referred by a physician, and upon entry, completed an exercise-based assessment and surveys to assess various quality of life measures. Participants were divided into two groups: lung cancer patients having undergone a lobectomy (LOB, n=9) or those diagnosed with all other cancers (AOC, n=201). Participants underwent 12weeks of supervised exercise based on an individualized exercise prescription. Measures of cardiorespiratory function, muscular strength, and quality of life were collected prior to the intervention and after 12weeks of exercise training. Significant improvements to VO2peak (p<0.05) were seen in both groups. Significant improvements to muscular strength (p<0.05) were seen in both groups for all measures aside from shoulder press in the LOB group. Both groups showed significant improvements to aspects of fatigue and quality of life (p<0.05), but only the AOC group significantly improved in measures of depression (p<0.05). Exercise-based rehabilitation is a safe and effective intervention for lung cancer survivors who have undergone a lobectomy. These individuals saw significant improvements in cardiorespiratory fitness, muscular strength, and quality of life. Although there were similarities in the pattern of these training-induced improvements for these groups, lung cancer patients undergoing a lobectomy consistently demonstrated lower absolute values when compared to patients with all other cancer diagnoses.

Endurance exercise training-responsive miR-19b-3p improves skeletal muscle glucose metabolism

Skeletal muscle is a highly adaptable tissue and remodels in response to exercise training. Using short RNA sequencing, we determine the miRNA profile of skeletal muscle from healthy male volunteers before and after a 14-day aerobic exercise training regime. Among the exercise training-responsive miRNAs identified, miR-19b-3p was selected for further validation. Overexpression of miR-19b-3p in human skeletal muscle cells increases insulin signaling, glucose uptake, and maximal oxygen consumption, recapitulating the adaptive response to aerobic exercise training. Overexpression of miR-19b-3p in mouse flexor digitorum brevis muscle enhances contraction-induced glucose uptake, indicating that miR-19b-3p exerts control on exercise training-induced adaptations in skeletal muscle. Potential targets of miR-19b-3p that are reduced after aerobic exercise training include KIF13A, MAPK6, RNF11, and VPS37A. Amongst these, RNF11 silencing potentiates glucose uptake in human skeletal muscle cells. Collectively, we identify miR-19b-3p as an aerobic exercise training-induced miRNA that regulates skeletal muscle glucose metabolism.

Aerobic exercise training reduces cardiac function and coronary flow-induced vasodilation in mice lacking adiponectin.

We tested the hypothesis that adiponectin deficiency attenuates cardiac and coronary microvascular function and prevents exercise training-induced adaptations of the myocardium and the coronary microvasculature in adult mice. Adult wild-type (WT) or adiponectin knockout (adiponectin KO) mice underwent treadmill exercise training or remained sedentary for 8-10 wk. Systolic and diastolic functions were assessed before and after exercise training or cage confinement. Vasoreactivity of coronary resistance arteries was assessed at the end of exercise training or cage confinement. Before exercise training, ejection fraction and fractional shortening were similar in adiponectin KO and WT mice, but isovolumic contraction time was significantly lengthened in adiponectin KO mice. Exercise training increased ejection fraction (12%) and fractional shortening (20%) with no change in isovolumic contraction time in WT mice. In adiponectin KO mice, both ejection fraction (-9%) and fractional shortening (-12%) were reduced after exercise training and these decreases were coupled to a further increase in isovolumic contraction time (20%). In sedentary mice, endothelium-dependent dilation to flow was higher in arterioles from adiponectin KO mice as compared with WT mice. Exercise training enhanced dilation to flow in WT mice but decreased flow-induced dilation in adiponectin KO mice. These data suggest that compensatory mechanisms contribute to the maintenance of cardiac and coronary microvascular function in sedentary mice lacking adiponectin; however, in the absence of adiponectin, cardiac and coronary microvascular adaptations to exercise training are compromised.NEW & NOTEWORTHY We report that compensatory mechanisms contribute to the maintenance of cardiac and coronary microvascular function in sedentary mice in which adiponectin has been deleted; however, when mice lacking adiponectin are subjected to the physiological stress of exercise training, beneficial coronary microvascular and cardiac adaptations are compromised or absent.

Exercise Training-Induced Extracellular Matrix Protein Adaptation in Locomotor Muscles: A Systematic Review

Exercise training promotes muscle adaptation and remodelling by balancing the processes of anabolism and catabolism; however, the mechanisms by which exercise delays accelerated muscle wasting are not fully understood. Intramuscular extracellular matrix (ECM) proteins are essential to tissue structure and function, as they create a responsive environment for the survival and repair of the muscle fibres. However, their role in muscle adaptation is underappreciated and underinvestigated. The PubMed, COCHRANE, Scopus and CIHNAL databases were systematically searched from inception until February 2021. The inclusion criteria were on ECM adaptation after exercise training in healthy adult population. Evidence from 21 studies on 402 participants demonstrates that exercise training induces muscle remodelling, and this is accompanied by ECM adaptation. All types of exercise interventions promoted a widespread increase in collagens, glycoproteins and proteoglycans ECM transcriptomes in younger and older participants. The ECM controlling mechanisms highlighted here were concerned with myogenic and angiogenic processes during muscle adaptation and remodelling. Further research identifying the mechanisms underlying the link between ECMs and muscle adaptation will support the discovery of novel therapeutic targets and the development of personalised exercise training medicine.

Impact of pre-exercise feeding status on metabolic adaptations to endurance-type exercise training.

Nutrition and exercise metabolism are vibrant physiological fields, yet at times it feels as if greater progress could be made by better integrating these disciplines. Exercise is advocated for improving metabolic health, in part by increasing peripheral insulin sensitivity and glycaemic control. However, when a modest-to-high carbohydrate load is consumed before and/or during each exercise bout within a training programme, increases in oral glucose insulin sensitivity can be blunted in both men of a healthy weight and those with overweight/obesity. Exercise training-induced adaptation in the energy sensing AMP-activated protein kinase (AMPK) and the insulin-sensitive glucose transporter GLUT4 protein levels are sensitive to pre-exercise feeding status in both healthy individuals and individuals classified as overweight or obese. Increased lipid oxidation may, in part, explain the enhanced adaptive responses to exercise training performed before (i.e. fasted-state exercise) versus after nutrient ingestion. Evidence in individuals with type 2 diabetes currently shows no effect of altering nutrient-exercise timing for measured markers of metabolic health, or greater reductions in glycated haemoglobin (HbA1c) concentrations with exercise performed after versus before nutrient provision. Since the metabolic inflexibility associated with type 2 diabetes diminishes differences in lipid oxidation between the fasted and fed states, it is plausible that pre-exercise feeding status does not alter adaptations to exercise when metabolic flexibility is already compromised. Current evidence suggests restricting carbohydrate intake before and during exercise can enhance some health benefits of exercise, but in order to establish clinical guidelines, further research is needed with hard outcomes and different populations.

Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.

What is the central question of this study? Does short-term high-intensity interval training alter the composition of the microbiome and is this associated with exercise-induced improvements in cardiorespiratory fitness and insulin sensitivity? What is the main finding and its importance? Although high-intensity interval training increased insulin sensitivity and cardiovascular fitness, it did not alter the composition of the microbiome. This suggests that changes in the composition of the microbiome that occur with prolonged exercise training might be in response to changes in metabolic health rather than driving exercise training-induced adaptations. Regular exercise reduces the risk of metabolic diseases, and the composition of the gut microbiome has been associated with metabolic function. We investigated whether short-term high-intensity interval training (HIIT) altered the diversity and composition of the bacterial community and whether there were associations with markers of insulin sensitivity or aerobic fitness. Cardiorespiratory fitness ( ) and body composition (dual energy X-ray absorptiometry scan) were assessed and faecal and fasted blood samples collected from 14 lean (fat mass 21±2%, aged 29±2years) and 15 overweight (fat mass 33±2%, aged 31±2years) men before and after 3weeks of HIIT training (8-12×60s cycle ergometer bouts at power output interspersed by 75s rest, three times per week). Gut microbiome composition was analysed by 16S rRNA gene amplicon sequencing. The HIIT significantly increased the aerobic fitness of both groups (P<0.001) and improved markers of insulin sensitivity (lowered fasted insulin and HOMA-IR; P<0.001) in the overweight group. Despite differences in the abundance of several bacterial taxa being evident between the lean and overweight group, HIIT did not affect the overall bacterial diversity or community structure (α-diversity or β-diversity). No associations were found between the top 50 most abundant bacterial genera and cardiorespiratory fitness markers; however, significant associations (P<0.05) were observed between the abundance of the bacterial species Coprococcus_3, Blautia, Lachnospiraceae_ge and Dorea and insulin sensitivity markers in the overweight group. Our results suggest that short-term HIIT does not greatly impact the overall composition of the gut microbiome, but that certain microbiome genera are associated with insulin sensitivity markers that were improved by HIIT in overweight participants.

The Role of Selenium Mineral Trace Element in Exercise: Antioxidant Defense System, Muscle Performance, Hormone Response, and Athletic Performance. A Systematic Review.

Exercise overproduces oxygen reactive species (ROS) and eventually exceeds the body’s antioxidant capacity to neutralize them. The ROS produce damaging effects on the cell membrane and contribute to skeletal muscle damage. Selenium (Se), a natural mineral trace element, is an essential component of selenoproteins that plays an important role in antioxidant defense. The activity of the enzyme glutathione peroxidase (GPx), a highly-efficient antioxidant enzyme, is closely dependent on the presence of Se. These properties of Se may be potentially applicable to improve athletic performance and training recovery. We systematically searched for published studies to evaluate the effectiveness of Se supplementation on antioxidant defense system, muscle performance, hormone response, and athletic performance among physically active individuals. We used the Preferred Reporting Elements for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and searched in SCOPUS, Web of Science (WOS), and PubMed databases to identify published studies until March 2020. The systematic review incorporated original studies with randomized controlled crossover or parallel design in which intake of Se administered once a day was compared with the same placebo conditions. No exclusions were applied for the type of physical exercise performed, the sex, nor the age of the participants. Among 150 articles identified in the search, 6 met the criteria and were included in the systematic review. The methodological quality of the studies was evaluated using the McMaster Critical Review Form. Oral Se supplementation with 180 µg/day or 240 µg/day (selenomethionine) and 200 µg/day (Sodium Selenite), significantly decreased lipid hydroperoxide levels and increased GPx in plasma, erythrocyte, and muscle. No significant effects were observed on athletic performance, testosterone hormone levels, creatine kinase activity, and exercise training-induced adaptations on oxidative enzyme activities or on muscle fiber type myosin heavy chain expression. In addition, Se supplementation showed to have a dampening effect on the mitochondria changes in chronic and acute exercise. In summary, the use of Se supplementation has no benefits on aerobic or anaerobic athletic performance but it may prevent Se deficiencies among athletes with high-intensity and high-volume training. Optimal Se plasma levels may be important to minimize chronic exercise-induced oxidative effects and modulate the exercise effect on mitochondrial changes.

Optimizing the Interaction of Exercise Volume and Metformin to Induce a Clinically Significant Reduction in Metabolic Syndrome Severity: A Randomised Trial.

Insulin resistance is a central mediating factor of the metabolic syndrome (MetS), with exercise training and metformin proven antidotes to insulin resistance. However, when the two therapies are combined there is conflicting data regarding whether metformin blunts or improves exercise training-induced adaptations. The volume of exercise (duration, intensity, and frequency) on the interaction of exercise training and metformin has yet to be investigated. The aim of this study is therefore to explore the impact of a combination of different exercise volumes and metformin on MetS severity. This is a secondary analysis of data from one of the sites of the ‘Exercise in Prevention of Metabolic Syndrome’ (EX-MET) study. Ninety-nine adults with MetS were randomized into a 16-week exercise program completing either: (i) moderate-intensity continuous training (MICT) at 60–70% of peak heart rate (HRpeak) for 30 min/session (n = 34, 150 min/week); (ii) high-volume high-intensity interval training (HIIT) consisting of 4 × 4 min bouts at 85–95% HRpeak, interspersed with 3 min of active recovery at 50–70% HRpeak (n = 34, 38 min/session, 114 min/week); or (iii) low volume HIIT, 1 × 4 min bout of HIIT at 85–95% HRpeak (n = 31, 17 min/session, 51 min/week). Metformin intake was monitored and recorded throughout the trial. MetS severity was calculated as z-scores derived from MetS risk factors assessed at pre- and post-intervention. Sixty-five participants had complete pre- and post-intervention data for MetS z-score, of which 18 participants (28%) were taking metformin. Over the 16-week intervention, a similar proportion of participants clinically improved MetS severity (Δ ≥ −0.87) with metformin (8/18, 44%) or without metformin (23/47, 49%) (p = 0.75). While there were no between-group differences (p = 0.24), in those who did not take metformin low-volume HIIT had more likely responders (10/15, 67%) compared to MICT (6/16, 38%) and high-volume HIIT (7/16, 44%). In those taking metformin, there was a lower proportion of participants who clinically improved MetS severity following high-volume HIIT (1/6, 17%) compared to MICT (2/4, 50%) and low-volume HIIT (5/8, 63%), but with no between-group difference (p = 0.23). Moreover, in those who performed high-volume HIIT, there was a statistically significantly higher proportion (p = 0.03) of likely non-responders with improved MetS severity in participants taking metformin (4/6, 67%) compared to those not taking metformin (3/16, 19%). In individuals with MetS, the effect of high volume HIIT on MetS severity may be blunted in those taking metformin. These findings need to be confirmed in a larger study.

Deficiency in ROS-sensing nuclear factor erythroid 2-like 2 causes altered glucose and lipid homeostasis following exercise training.

Oxidative stress induced by acute exercise may regulate exercise training-induced adaptations that improve metabolic health. One of the central transcription regulatory targets of reactive oxygen species (ROS) is Nrf2 (nuclear factor erythroid-derived 2-like 2, or NFE2L2). Here, we investigated whether global deficiency of Nrf2 in mice would impact exercise training-induced changes in glucose and lipid homeostasis. We report that following 6 wk of treadmill exercise training, Nrf2-deficient mice have elevated fasting plasma triglycerides and free fatty acids and higher blood glucose levels following a meal despite having a similar fat mass to wild-type controls. This impaired glucose homeostasis appears to be related to reduced insulin sensitivity primarily in adipose and liver tissue, and although a clear mechanism was not evident, Nrf2-deficient mice had increased markers of hepatic oxidative stress and stress-related kinase activation in white adipose tissue (WAT) without overt inflammation alteration in WAT or modulation of hepatic and WAT fibroblast growth factor 21 gene expression. Our results suggest that Nrf2 facilitates exercise training-induced improvements in glucose homeostasis; however, further research is required to determine whether this occurs through direct regulation of exercise adaptations or via the maintenance of redox balance during training.

High-intensity exercise training enhances mitochondrial oxidative phosphorylation efficiency in a temperature-dependent manner in human skeletal muscle: implications for exercise performance.

The purpose of the present study was to investigate whether exercise training-induced adaptations in human skeletal muscle mitochondrial bioenergetics are magnified under thermal conditions resembling sustained intense contractile activity and whether training-induced changes in mitochondrial oxidative phosphorylation (OXPHOS) efficiency influence exercise efficiency. Twenty healthy men performed 6 wk of high-intensity exercise training [i.e., speed endurance training (SET; n = 10)], or maintained their usual lifestyle (n = 10). Before and after the intervention, mitochondrial respiratory function was determined ex vivo in permeabilized muscle fibers under experimentally-induced normothermia (35°C) and hyperthermia (40°C) mimicking in vivo muscle temperature at rest and during intense exercise, respectively. In addition, activity and content of muscle mitochondrial enzymes and proteins were quantified. Exercising muscle efficiency was determined in vivo by measurements of leg hemodynamics and blood parameters during one-legged knee-extensor exercise. SET enhanced maximal OXPHOS capacity and OXPHOS efficiency at 40°C, but not at 35°C, and attenuated hyperthermia-induced decline in OXPHOS efficiency. Furthermore, SET increased expression of markers of mitochondrial content and up-regulated content of MFN2, DRP1, and ANT1. Also, SET improved exercise efficiency and capacity. These findings indicate that muscle mitochondrial bioenergetics adapts to high-intensity exercise training in a temperature-dependent manner and that enhancements in mitochondrial OXPHOS efficiency may contribute to improving exercise performance.-Fiorenza, M., Lemminger, A. K., Marker, M., Eibye, K., Iaia, F. M., Bangsbo, J., Hostrup, M. High-intensity exercise training enhances mitochondrial oxidative phosphorylation efficiency in a temperature-dependent manner in human skeletal muscle: implications for exercise performance.

Deficiency of the transcription factor, Nrf2, impairs vasomotor responses and limits exercise training‐induced adaptations of coronary arterioles

Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is a transcription factor that is crucial in maintaining cellular redox homeostasis. Vasomotor responses of the coronary resistance vasculature and regulation of coronary blood flow are closely linked to myocardial metabolism and redox status of the myocardium. We hypothesized that deletion of Nrf2 would alter vascular responses of coronary arterioles and limit exercise training‐induced adaptations of vasomotor function. We exercise trained wild type (WT) Sprague‐Dawley rats, and their littermates that were lacking the Nrf2 gene (Nrf2KO). Rats were either exercise trained (EX) on a motor‐driven treadmill 5 days/wk or remained sedentary (SED) in their cages for 10–12 weeks. A mixed moderate aerobic and high‐intensity interval training protocol was utilized. At the end of the training period, coronary arterioles were isolated for assessment of vasomotor responses to potassium chloride (KCl) and endothelin, as both are considered potential endogenous regulators of coronary vascular resistance. We also evaluated responsiveness of coronary arterioles to increasing intraluminal pressure (the myogenic response). Contractile responses of coronary arterioles to KCl and endothelin were reduced in arterioles from sedentary Nrf2KO rats as compared to arterioles from sedentary WT rats. Low concentrations of KCl induced vasodilation in coronary arterioles from exercise trained WT rats but not in arterioles from sedentary WT rats. Constriction to high concentrations of KCl was reduced in arterioles from exercise trained WT rats as compared to those from sedentary WT (WT EX vs WT SED; P&lt;0.01); however, these adaptations to exercise training were absent in arterioles from Nrf2KO rats (KO EX vs KO SED; P=0.94). Exercise training altered vasoconstrictor responses to endothelin in coronary arterioles from both WT and Nrf2KO rats; however, the effects of exercise training were directionally opposite in arterioles from WT and Nrf2KO rats. In arterioles from WT rats, exercise training reduced vasoconstrictor responses to endothelin, whereas in arterioles from Nrf2KO rats, vasoconstrictor responses to endothelin were increased by exercise training. Myogenic responsiveness was decreased in coronary arterioles from Nrf2KO rats as compared to arterioles from WT rats, but exercise training did not alter myogenic responsiveness in arterioles from either WT or Nrf2KO rats. These data suggest that the contractile responsiveness of coronary arterioles is decreased in the absence of Nrf2. The absence of Nrf2 also limits adaptation of coronary arterioles in response to exercise training. These changes in arteriolar function may be linked to alterations of redox homeostasis and metabolite production in cardiac muscle that is deficient in Nrf2.Support or Funding InformationNIH R15AG055029This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

PO-033 Mitochondria-associated Ampk mediates mitochondrial quality control in skeletal muscle

Objective Mitochondria exist as a complex, interconnected reticulum with the degree of complexity at homeostasis varying by cell type. Declines in mitochondrial quality is a hallmark of numerous diseases and is partly maintained through the targeted removal and degradation of damaged/dysfunctional regions of the reticulum known as mitophagy. We have demonstrated that acute exercise causes targeted degradation of a subset (&lt;1%) of the mitochondrial reticulum through mitophagy in an AMPK-dependent manner. However, how such spatial regulation is achieved is unclear. Given that AMPK is a well-known bioenergetics sensor critical for maintenance of energetic homoeostasis, and numerous studies have linked AMPK-signaling to mitochondrial remodeling and functional adaptations under physiological and pathological conditions, we hypothesized that AMPK regulates mitophagy by being physically associated with the mitochondria. &#x0D; Methods C57BL/6 mice (3 or 20 months of age) were kept in standard conditions (12:12 light, dark cycle) on normal chow. Enriched mitochondrial fractions from skeletal muscle were obtained via differential centrifugation and percoll gradient isolation. Skeletal muscle energetic stress was induced via acute treadmill running, direct electrical stimulation, or hindlimb ischemia-reperfusion. Somatic gene transfer into skeletal muscle was done via electraporation. Confocal microscopy of whole mount skeletal muscle was performed at least 10 days post-electraporation to assess MitoTimer fluorescence Red:Green Ratio and Mitophagy (i.e. presence of pure red puncta).&#x0D; Results We have discovered that AMPK is enriched in isolated mitochondria from both mouse and human skeletal muscle (mitoAMPK) and that, in mice, mitoAMPK consists exclusively of ⍺1/β2/γ1 isoforms. Furthermore, skeletal muscle mitoAMPK Thr172 phosphorylation, indicative of activation, is increased following electrical stimulation, ischemia-reperfusion, and acute treadmill running. By co-transfecting mouse FDB muscle with pMitoTimer and a mitochondrially-targeted AMPK inhibitor peptide (mitoAIP), we show that mitoAMPK activity is required to maintain mitochondrial quality (as evidenced by increased MitoTimer Red:Green ratio) and exercise-induced mitophagy (MitoTimer pure red puncta). Interestingly, association of mitoAMPK with mitochondria declines by ~50% in skeletal muscle in old mice and coincides with poor mitochondrial quality (increased MitoTimer Red:Green ratio), which may explain the loss of mitochondrial quality and metabolic flexibility with aging.&#x0D; Conclusions Our current working hypothesis is that activation of mitoAMPK by exercise plays an instrumental role in promoting mitochondrial remodeling, hence contractile and metabolic adaptations, by spatially recognizing damaged regions of the mitochondrial reticulum. Future research on mitoAMPK will significantly improve the mechanistic understanding of exercise training-induced adaptation in skeletal muscle and AMPK biology.

The role of adiponectin in exercise training‐induced vascular adaptation

We have previously reported that in old rats, reversal of age‐related vascular dysfunction by exercise training correlates with an increase in circulating adiponectin and its signaling within coronary vascular smooth muscle. In the current study, we investigated the effect of deletion of adiponectin on exercise training‐induced vascular adiponectin. C57BL/6 wild‐type (WT) or homozygous adiponectin knockout (AdipoKO) mice were obtained at 10–12 wks of age and underwent treadmill exercise training (EX) (12 m/min, 5° incline, 1 hr/day, 5 days/wk for 8 wks) or remained sedentary (SED) in cages. Arterioles isolated from cardiac and soleus muscle were assessed for contractile and vasodilatory function, and capillarity of the soleus muscle was evaluated. Exercise training increased flow‐induced dilation significantly in coronary arterioles of WT mice (P&lt;0.01 EX vs. SED), but decreased flow‐induced dilation in coronary arterioles from AdipoKO mice. ACh‐induced dilation was reduced in coronary arterioles from AdipoKO mice as compared to those from WT mice (P&lt;0.05 AdipoKO vs. WT). Exercise training reduced ACh‐induced dilation in arterioles from WT mice, but increased ACh‐induced dilation in arterioles from AdipoKO mice. Baseline capillarity increased in the soleus muscle of AdipoKO mice as compared to WT mice, but an exercise training‐induced increase in capillarity, detected in WT mice, was absent in AdipoKO mice. Contractile responsiveness to phenylephrine was increased in arterioles from the soleus muscle of both WT and AdipoKO mice (P&lt;0.01 EX vs. SED in both WT and AdipoKO). These data indicate that adiponectin is a critical contributor to exercise training‐induced vascular adaptations; however, locally produced adiponectin may be more critical than circulating adiponectin in mediating these adaptations.Support or Funding InformationFlorida State University College of MedicineThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Inter-individual variation in adaptations to endurance and resistance exercise training: genetic approaches towards understanding a complex phenotype

Exercise training which meets the recommendations set by the National Physical Activity Guidelines ensues a multitude of health benefits towards the prevention and treatment of various chronic diseases. However, not all individuals respond well to exercise training. That is, some individuals have no response, while others respond poorly. Genetic background is known to contribute to the inter-individual (human) and -strain (e.g., mice, rats) variation with acute exercise and exercise training, though to date, no specific genetic factors have been identified that explain the differential responses to exercise. In this review, we provide an overview of studies in human and animal models that have shown a significant contribution of genetics in acute exercise and exercise training-induced adaptations with standardized endurance and resistance training regimens, and further describe the genetic approaches which have been used to demonstrate such responses. Finally, our current understanding of the role of genetics and exercise is limited primarily to the nuclear genome, while only a limited focus has been given to a potential role of the mitochondrial genome and its interactions with the nuclear genome to predict the exercise training-induced phenotype(s) responses. We therefore discuss the mitochondrial genome and literature that suggests it may play a significant role, particularly through interactions with the nuclear genome, in the inherent ability to respond to exercise.

Voluntary exercise and depression-like behavior in rodents: are we running in the right direction?

Acute or chronic exposure to stress can increase the risk to develop major depressive disorder, a severe, recurrent and common psychiatric condition. Depression places an enormous social and financial burden on modern society. Although many depressed patients are treated with antidepressants, their efficacy is only modest, underscoring the necessity to develop clinically effective pharmaceutical or behavioral treatments. Exercise training produces beneficial effects on stress-related mental disorders, indicative of clinical potential. The pro-resilient and antidepressant effects of exercise training have been documented for several decades. Nonetheless, the underlying molecular mechanisms and the brain circuitries involved remain poorly understood. Preclinical investigations using voluntary wheel running, a frequently used rodent model that mimics aspects of human exercise training, have started to shed light on the molecular adaptations, signaling pathways and brain nuclei underlying the beneficial effects of exercise training on stress-related behavior. In this review, I highlight several neurotransmitter systems that are putative mediators of the beneficial effects of exercise training on mental health, and review recent rodent studies that utilized voluntary wheel running to promote our understanding of exercise training-induced central adaptations. Advancements in our mechanistic understanding of how exercise training induces beneficial neuronal adaptations will provide a framework for the development of new strategies to treat stress-associated mental illnesses.

PGC-1α and exercise intensity dependent adaptations in mouse skeletal muscle

The aim of the present study was to examine the role of PGC-1α in intensity dependent exercise and exercise training-induced metabolic adaptations in mouse skeletal muscle. Whole body PGC-1α knockout (KO) and littermate wildtype (WT) mice performed a single treadmill running bout at either low intensity (LI) for 40 min or moderate intensity (MI) for 20 min. Blood and quadriceps muscles were removed either immediately after exercise or at 3h or 6h into recovery from exercise and from resting controls. In addition PGC-1α KO and littermate WT mice were exercise trained at either low intensity (LIT) for 40 min or at moderate intensity (MIT) for 20 min 2 times pr. day for 5 weeks. In the first and the last week of the intervention period, mice performed a graded running endurance test. Quadriceps muscles were removed before and after the training period for analyses. The acute exercise bout elicited intensity dependent increases in LC3I and LC3II protein and intensity independent decrease in p62 protein in skeletal muscle late in recovery and increased LC3II with exercise training independent of exercise intensity and volume in WT mice. Furthermore, acute exercise and exercise training did not increase LC3I and LC3II protein in PGC-1α KO. In addition, exercise-induced mRNA responses of PGC-1α isoforms were intensity dependent. In conclusion, these findings indicate that exercise intensity affected autophagy markers differently in skeletal muscle and suggest that PGC-1α regulates both acute and exercise training-induced autophagy in skeletal muscle potentially in a PGC-1α isoform specific manner.