Impacts of altered exercise volume, intensity, and duration on the activation of AMPK and CaMKII and increases in PGC-1α mRNA.

The purpose of this review is to explore and discuss the impacts of augmented training volume, intensity, and duration on the phosphorylation/activation of key signaling protein - AMPK, CaMKII and PGC-1α - involved in the initiation of mitochondrial biogenesis. Specifically, we explore the impacts of augmented exercise protocols on AMP/ADP and Ca2+ signaling and changes in post exercise PGC - 1α gene expression. Although AMP/ADP concentrations appear to increase with increasing intensity and during extended durations of higher intensity exercise AMPK activation results are varied with some results supporting and intensity/duration effect and others not. Similarly, CaMKII activation and signaling results following exercise of different intensities and durations are inconsistent. The PGC-1α literature is equally inconsistent with only some studies demonstrating an effect of intensity on post exercise mRNA expression. We present a novel meta-analysis that suggests that the inconsistency in the PGC-1α literature may be due to sample size and statistical power limitations owing to the effect of intensity on PGC-1α expression being small. There is little data available regarding the impact of exercise duration on PGC-1α expression. We highlight the need for future well designed, adequately statistically powered, studies to clarify our understanding of the effects of volume, intensity, and duration on the induction of mitochondrial biogenesis by exercise.

Differential changes in appetite hormones post-prandially based on menstrual cycle phase and oral contraceptive use: A preliminary study.

This was a preliminary study that examined whether appetite regulation is altered during the menstrual cycle or with oral contraceptives. Ten naturally cycling females (NON-USERS) and nine tri-phasic oral contraceptive using females (USERS) completed experimental sessions during each menstrual phase (follicular phase: FP; ovulatory phase: OP; luteal phase: LP). Appetite perceptions and blood samples were obtained fasted, 30, 60, and 90 min post-prandial to measure acylated ghrelin, active glucagon-like peptide-1 (GLP-1), and total peptide tyrosine tyrosine (PYY). Changes were considered important if p < 0.100 and the effect size was ≥medium. There appeared to be a three-way (group x phase x time) interaction for acylated ghrelin where concentrations appeared to be greater in USERS versus NON-USERS during the OP 90-min post-prandial and during the LP fasted, and 90-min post-prandial. In USERS, ghrelin appeared to be greater 90-min post-prandial in the OP versus the FP with no other apparent differences between phases. There were no apparent differences between phases in NON-USERS. There appeared to be a three-way interaction for PYY where concentrations appeared to be greater in USERS during the FP 60-min post-prandial and during the OP 30-min post-prandial. In USERS PYY appeared to be greater 60-min post-prandial during the OP versus the LP with no other apparent differences. There were no apparent differences between phases in NON-USERS. There appeared to be no effect of group or phase on GLP-1, or appetite perceptions. These data demonstrate small effects of menstrual cycle phase and oral contraceptive use on the acylated ghrelin and total PYY response to a standardized meal, with no effects on active GLP-1 or perceived appetite, though more work with a large sample size is necessary.

No acute hyperglycemia induced impairment in brachial artery flow-mediated dilation before or after aerobic exercise training in young recreationally active males.

There is some evidence that transient endothelial dysfunction induced by acute hyperglycemia may be attenuated by a single bout of aerobic exercise. However, the impact of aerobic exercise training on acute hyperglycemia-induced endothelial dysfunction has not been explored. The purpose of this study was to determine the impact of aerobic exercise training on the endothelial function response to acute hyperglycemia. Brachial artery flow-mediated dilation (FMD) was assessed in 24 healthy males (21 ± 1 years) pre-, 60 and 90 min post ingestion of 75 g of glucose. Participants completed a four-week control (CON; n = 13) or exercise training (EX; n = 11) intervention. The EX group completed four weeks of cycling exercise (30 min, 4×/week at 65% work rate peak). Cardiorespiratory fitness ([Formula: see text]O2peak) increased and resting HR decreased in EX, but not CON post-intervention (p < 0.001). Glucose and insulin increased (p < 0.001) following glucose ingestion, with no significant difference pre- and post-intervention. In contrast to previous research, FMD was unaffected by glucose-ingestion, pre- and post-intervention in both groups. In conclusion, acute hyperglycemia did not impair endothelial function, before or after exercise training. Relatively high baseline fitness ([Formula: see text]O2peak ~ 46 mL/kg/min) and young age may have contributed to the lack of impairment observed. Further research is needed to examine the impact of exercise training on hyperglycemia-induced impairments in endothelial function in sedentary males and females.

Directions for Exercise Treatment Response Heterogeneity and Individual Response Research.

Treatment response heterogeneity and individual responses following exercise training are topics of interest for personalized medicine. Proposed methods to determine the contribution of exercise to the magnitude of treatment response heterogeneity and categorizing participants have expanded and evolved. Setting clear research objectives and having a comprehensive understanding of the strengths and weaknesses of the available methods are vital to ensure the correct study design and analytical approach are used. Doing so will ensure contributions to the field are conducted as rigorously as possible. Nonetheless, concerns have emerged regarding the ability to truly isolate the impact of exercise training, and the nature of individual responses in relation to mean group changes. The purpose of this review is threefold. First, the strengths and limitations associated with current methods for quantifying the contribution of exercise to observed treatment response heterogeneity will be discussed. Second, current methods used to categorize participants based on their response to exercise will be outlined, as well as proposed mechanisms for factors that contribute to response variation. Finally, this review will provide an overview of some current issues at the forefront of individual response research.

Increasing whole-body energetic stress does not augment fasting-induced changes in human skeletal muscle.

Fasting rapidly (≤ 6 h) activates mitochondrial biogenic pathways in rodent muscle, an effect that is absent in human muscle following prolonged (10-72 h) fasting. We tested the hypotheses that fasting-induced changes in human muscle occur shortly after food withdrawal and are modulated by whole-body energetic stress. Vastus lateralis biopsies were obtained from ten healthy males before, during (4 h), and after (8 h) two supervised fasts performed with (FAST+EX) or without (FAST) 2 h of arm ergometer exercise (~ 400 kcal of added energy expenditure). PGC-1α mRNA (primary outcome measure) was non-significantly reduced (p = 0.065 [ηp2 = 0.14]) whereas PGC-1α protein decreased (main effect of time: p < 0.01) during both FAST and FAST+EX. P53 acetylation increased in both conditions (main effect of time: p < 0.01) whereas ACC and SIRT1 phosphorylation were non-significantly decreased (both p < 0.06 [ηp2 = 0.15]). Fasting-induced increases in NFE2L2 and NRF1 protein were observed (main effects of time: p < 0.03), though TFAM and COXIV protein remained unchanged (p > 0.05). Elevating whole-body energetic stress blunted the increase in p53 mRNA, which was apparent during FAST only (condition × time interaction: p = 0.04). Select autophagy/mitophagy regulators (LC3BI, LC3BII, BNIP3) were non-significantly reduced at the protein level (p ≤ 0.09 [ηp2 > 0.13]) but the LC3II:I ratio was unchanged (p > 0.05). PDK4 mRNA (p < 0.01) and intramuscular triglyceride content in type IIA fibers (p = 0.04) increased similarly during both conditions. Taken together, human skeletal muscle signaling, mRNA/protein expression, and substrate storage appear to be unaffected by whole-body energetic stress during the initial hours of fasting.

Genome wide association study of response to interval and continuous exercise training: the Predict-HIIT study.

BACKGROUND: Low cardiorespiratory fitness (V̇O2peak) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve V̇O2peak, there is considerable inter-individual variability in the V̇O2peak response to the same dose of exercise. Understanding how genetic factors contribute to V̇O2peak training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of V̇O2peak response following exercise training. METHODS: Participant change in objectively measured V̇O2peak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated (P < 1 × 10-5) with the magnitude of V̇O2peak response. Findings were tested in an independent validation study (n = 39) and compared to previous research. RESULTS: No variants at the genome-wide significance level were found after adjusting for key covariates (baseline V̇O2peak, individual study, principal components which were significantly associated with the trait). A Quantile-Quantile plot indicates there was minor inflation in the study. Twelve novel loci showed a trend of association with V̇O2peak response that reached suggestive significance (P < 1 × 10-5). The strongest association was found near the membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2) gene (rs6959961, P = 2.61 × 10-7). A PPS created from the 12 lead SNPs was unable to predict V̇O2peak response in a tenfold cross validation, or in an independent (n = 39) validation study (P > 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT (P < 1 × 10-4) and the validation study (P < × 10-6), indicating that general effects of the loci exist, and that with a higher statistical power, more significant genetic associations may become apparent. CONCLUSIONS: Ongoing research and validation of current and previous findings is needed to determine if genetics does play a large role in V̇O2peak response variance, and whether genomic predictors for V̇O2peak response trainability can inform evidence-based clinical practice. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), Trial Id: ACTRN12618000501246, Date Registered: 06/04/2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374601&isReview=true .

Examining interindividual differences in select muscle and whole-body adaptations to continuous endurance training.

NEW FINDINGS: What is the central question of the study? Do interindividual differences in trainability exist for morphological and molecular skeletal muscle responses to aerobic exercise training? What is the main finding and its importance? Interindividual differences in trainability were present for some, but not all, morphological and molecular outcomes included in our study. Our findings suggest that it is inappropriate, and perhaps erroneous, to assume that variability in observed responses reflects interindividual differences in trainability in skeletal muscle responses to aerobic exercise training. ABSTRACT: Studies have interpreted a wide range of morphological and molecular changes in human skeletal muscle as evidence of interindividual differences in trainability. However, these interpretations fail to account for the influence of random measurement error and within-subject variability. The purpose of the present study was to use the standard deviation of individual response (SDIR ) statistic to test the hypothesis that interindividual differences in trainability are present for some but not all skeletal muscle outcomes. Twenty-nine recreationally active males (age: 21 ± 2 years; BMI: 24 ± 3 kg/m2 ; V̇O2peak ; 45 ± 7 ml/kg/min) completed 4 weeks of continuous training (REL; n = 14) or control (n = 15). Maximal enzyme activities (citrate synthase and ß-hydroxyacyl-CoA dehydrogenase), capillary density, fibre type composition, fibre-specific succinate dehydrogenase activity and substrate storage (intramuscular triglycerides and glycogen), and markers of mitophagy (BCL2-interacting protein 3 (BNIP3), BNIP3-like protein, parkin and PTEN-induced kinase 1) were measured in vastus lateralis samples collected before and after the intervention. We also calculated SDIR values for V̇O2peak , peak work rate and the onset of blood lactate accumulation for the REL group and a separate group that exercised at the negative talk test stage. Although positive SDIR values - indicating interindividual differences in trainability - were obtained for aerobic capacity outcomes, maximal enzyme activities, capillary density, all fibre-specific outcomes and BNIP3 protein content, the remaining outcomes produced negative SDIR values indicating a large degree of random measurement error and/or within-subject variability. Our findings question the interpretation of heterogeneity in observed responses as evidence of interindividual differences in trainability and highlight the importance of including control groups when analysing individual skeletal muscle response to exercise training.

Molecular regulation of skeletal muscle mitochondrial biogenesis following blood flow-restricted aerobic exercise: a call to action.

Blood flow-restricted (BFR) exercise can induce training adaptations comparable to those observed following training in free flow conditions. However, little is known about the acute responses within skeletal muscle following BFR aerobic exercise (AE). Moreover, although preliminary evidence suggests chronic BFR AE may augment certain training adaptations in skeletal muscle mitochondria more than non-BFR AE, the underlying mechanisms are poorly understood. In this review, we summarise the acute BFR AE literature examining mitochondrial biogenic signalling pathways and provide insight into mechanisms linked to skeletal muscle remodelling following BFR AE. Specifically, we focus on signalling pathways potentially contributing to augmented peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) mRNA following work-rate-matched BFR AE compared with non-BFR AE. We present evidence suggesting reductions in muscle oxygenation during acute BFR AE lead to increased intracellular energetic stress, AMP-activated protein kinase (AMPK) activation and PGC-1α mRNA. In addition, we briefly discuss mitochondrial adaptations to BFR aerobic training, and we assess the risk of bias using the Cochrane Collaboration risk of bias assessment tool. We ultimately call for several straightforward modifications to help minimise bias in future BFR AE studies.

Individual patterns of response to traditional and modified sprint interval training.

We compared the incidence of response between a traditional sprint interval training (SIT) protocol (30:240: 4-6 x 30-s, 240-s recovery) and 2 modified SIT protocols (15:120: 8-12 x 15-s, 120-s recovery; 5:40: 24-36 x 5-s, 40-s recovery) over 4 weeks of training in 84 recreationally active individuals (n = 23 per SIT group/15 control participants). Pre- and post-testing measures included V. O2max, 5-km time trial, and anaerobic capacity. Responders were classified using 2x typical error and seven other approaches to explore the impact of classification method on response rates. There was no difference in the proportion (2x typical error) of V.O2max responders across groups (30:240: 64%; 15:120: 39%; 5:40: 41%; CTRL: 33%; P= 0.190). The 30:240 group had more responders (P< 0.05) for time trial performance (70%) and peak speed during the 30 s running test (48%) compared to CTRL (21% and 0%, respectively). There were no other between-group differences (P> 0.112). Approaches with the largest response thresholds resulted in the fewest responders highlighting response rates are influenced by the method used. Additionally, we observed intra-individual differences in responsiveness across outcomes. This is the first study to empirically test the difference in the incidence of response and demonstrate individual patterns of response across different SIT protocols.

Fiber-specific and whole-muscle LRP130 expression in rested, exercised, and fasted human skeletal muscle.

Leucine-rich pentatricopeptide repeat motif-containing protein (LRP130) is implicated in the control of mitochondrial gene expression and oxidative phosphorylation in the liver, partly due to its interaction with peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α). To investigate LRP130's role in healthy human skeletal muscle, we examined LRP130's fiber-type distribution and subcellular localization (n = 6), as well as LRP130's relationship with PGC-1α protein and citrate synthase (CS) maximal activity (n = 33) in vastus lateralis samples obtained from young males. The impact of an acute bout of exercise (endurance [END] and sprint interval training [SIT]) and fasting (8 h) on LRP130 and PGC-1α expression was also determined (n = 10). LRP130 protein content paralleled fiber-specific succinate dehydrogenase activity (I > IIA) and strongly correlated with the mitochondrially localized protein apoptosis-inducing factor in type I (r = 0.75) and type IIA (r = 0.85) fibers. Whole-muscle LRP130 protein content was positively related to PGC-1α protein (r = 0.49, p < 0.01) and CS maximal activity (r = 0.42, p < 0.01). LRP130 mRNA expression was unaltered (p > 0.05) following exercise, despite ~ 6.6- and ~ 3.8-fold increases (p < 0.01) in PGC-1α mRNA expression after END and SIT, respectively. Although unchanged at the group level (p > 0.05), moderate-to-strong positive correlations were apparent between individual changes in LRP130 and PGC-1α expression at the mRNA (r = 0.63, p < 0.05) and protein (r = 0.59, p = 0.07) level in response to fasting. Our findings support a potential role for LRP130 in the maintenance of basal mitochondrial phenotype in human skeletal muscle. LRP130's importance for mitochondrial remodeling in exercised and fasted human skeletal muscle requires further investigation.

The impact of acute and chronic exercise on Nrf2 expression in relation to markers of mitochondrial biogenesis in human skeletal muscle.

PURPOSE: To examine the relationship between changes in nuclear factor erythroid 2-related factor 2 (Nrf2) expression and markers of mitochondrial biogenesis in acutely and chronically exercised human skeletal muscle. METHODS: The impact of acute submaximal endurance (END) and supramaximal interval (Tabata) cycling on the upregulation of Nrf2 (and its downstream targets), nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor A (TFAM) mRNA expression was examined in healthy young males (n = 10). The relationship between changes in citrate synthase (CS) maximal activity and the protein content of Nrf2, heme oxygenase 1 (HO-1), NRF-1, and TFAM was also investigated following 4 weeks of Tabata in a separate group of males (n = 21). RESULTS: Nrf2, NRF-1, and HO-1 mRNA expression increased after acute exercise (p < 0.05), whereas the increase in superoxide dismutase 2 (SOD2) mRNA expression approached significance (p = 0.08). Four weeks of Tabata increased CS activity and Nrf2, NRF-1, and TFAM protein content (p < 0.05), but decreased HO-1 protein content (p < 0.05). Training-induced changes in Nrf2 protein were strongly correlated with NRF-1 (r = 0.63, p < 0.01). When comparing protein content changes between individuals with the largest (HI: + 23%) and smallest (LO: - 1%) observed changes in CS activity (n = 8 each), increases in Nrf2 and TFAM protein content were apparent in the HI group only (p < 0.02) with medium-to-large effect sizes for between-group differences in changes in Nrf2 (ηp2=0.15) and TFAM (ηp2 = 0.12) protein content. CONCLUSION: Altogether, our findings support a potential role for Nrf2 in exercise-induced mitochondrial biogenesis in human skeletal muscle.

Gene expression variability in human skeletal muscle transcriptome responses to acute resistance exercise.

NEW FINDINGS: What is the central question of this study? Does exercise, independent of random error and within-subject variability, contribute to the variability in gene expression responses to an acute bout of resistance exercise? What is the main finding and its importance? A reanalysis of publicly available microarray data revealed that variability in observed gene expression responses for a subset of genes could be partially attributable to an effect of acute resistance exercise. These finding support the notion that individual responsiveness explains a portion of the variability in observed gene expression responses to acute resistance exercise. ABSTRACT: The purpose of this study was to use publicly available transcriptomic data to determine whether variability in gene expression responses to an acute bout of acute resistance exercise (ARE) can be attributable to an effect of ARE per se. We examined microarray data from a previous study that collected skeletal muscle biopsies before and 24 h after ARE or a no-exercise time-matched control period (CTL). By subtracting the standard deviation in the observed responses to CTL from ARE, we determined that ARE contributed to the variability in the observed gene expression responses for many (∼31,000), but not all, transcripts included on the Affymetrix Human Genome chips. ARE had a large effect on variability in the observed gene expression responses in 1290 genes that was not attributed to any technical/biological variability associated with repeated measurements. Pathway analysis using WebGestalt revealed that several of these 1290 genes are involved in pathways known to regulate skeletal muscle adaptations to chronic resistance training. These results suggest that variability in the observed gene expression responses for a subset of genes could be partially attributable to an effect of ARE.

Repeatability of exercise-induced changes in mRNA expression and technical considerations for qPCR analysis in human skeletal muscle.

NEW FINDINGS: What is the central question of this study? Are individual changes in exercise-induced mRNA expression repeatable (i.e. representative of the true response to exercise rather than random error)? What is the main finding and its importance? Exercise-induced changes in mRNA expression are not repeatable even under identical experimental conditions, thereby challenging the use of mRNA expression as a biomarker of adaptive potential and/or individual responsiveness to exercise. ABSTRACT: It remains unknown if (1) the observed change in mRNA expression reflects an individual's true response to exercise or random (technical and/or biological) error, and (2) the individual responsiveness to exercise is protocol-specific. We examined the repeatability of skeletal muscle PGC-1α, PDK4, NRF-1, VEGF-A, HSP72 and p53 mRNA expression following two identical endurance exercise (END) bouts (END-1, END-2; 30 min of cycling at 65% of peak work rate (WRpeak ), n = 11) and inter-individual variability in PGC-1α and PDK4 mRNA expression following END and sprint interval training (SIT; 8 × 20 s cycling intervals at ∼170% WRpeak , n = 10) in active young males. The repeatability of key gene analysis steps (RNA extraction, reverse transcription, qPCR) and within-sample fibre-type distribution (n = 8) was also determined to examine potential sources of technical error in our analyses. Despite highly repeatable exercise bout characteristics (work rate, heart rate, blood lactate; ICC > 0.71; CV < 10%; r > 0.85, P < 0.01), gene analysis steps (ICC > 0.73; CV < 24%; r > 0.75, P < 0.01), and similar group-level changes in mRNA expression, individual changes in PGC-1α, PDK4, VEGF-A and p53 mRNA expression were not repeatable (ICC < 0.22; CV > 20%; r < 0.21). Fibre-type distribution in two portions of the same muscle biopsy was highly variable and not significantly related (ICC = 0.39; CV = 26%; r = 0.37, P = 0.37). Since individual changes in mRNA expression following identical exercise bouts were not repeatable, inferences regarding individual responsiveness to END or SIT were not made. Substantial random error exists in changes in mRNA expression following acute exercise, thereby challenging the use of mRNA expression for analysing individual responsiveness to exercise.

The application of repeated testing and monoexponential regressions to classify individual cardiorespiratory fitness responses to exercise training.

PURPOSE: We tested the hypothesis that monoexponential regressions will increase the certainty in response estimates and confidence in classification of cardiorespiratory fitness (CRF) responses compared to a recently proposed linear regression approach. METHODS: We used data from a previously published RCT that involved 24 weeks of training at high amount-high intensity (HAHI; N = 28), high amount-low intensity (HALI; N = 48), or low amount-low intensity (LALI; N = 33). CRF was measured at 0, 4, 8, 16, and 24 weeks. We fit the repeated CRF measures with monoexponential and linear regressions, and calculated individual response estimates, the error in these estimates (TEMONOEXP and TESLOPE, respectively), and 95% confidence intervals (CIs). Individuals were classified as responders, uncertain, or non-responders based on where their CI lay relative to a minimum clinically important difference. Additionally, responses were classified using observed pre-post-changes and the typical error of measurement. RESULTS: Comparing the error in response estimates revealed that monoexponential regressions were a better fit than linear regressions for the majority of individual responses (N = 81/109) and mean CRF data (mean TEMONOEXP:TESLOPE; HAHI = 2.00:2.58, HALI = 1.91:2.46, LALI = 1.63:2.18; all p < 0.01). Fewer individuals were confidently classified as responders with linear regressions (N = 29/109) compared to monoexponential (N = 55/109). Additionally, response estimates were highly correlated across all three approaches (all r > 0.92). CONCLUSIONS: Future studies should determine the type of regression that best fits their data prior to classifying responses. The similarity in response estimates and classification from regressions and observed pre-post-changes questions the purported benefit of using repeated measures to characterize CRF responses to training.

The influence of vitamin C on the interaction between acute mental stress and endothelial function.

PURPOSE: To determine whether orally administered vitamin C attenuates expected mental stress-induced reductions in brachial artery endothelial function as measured by flow-mediated dilation (FMD). METHODS: Fifteen men (21 ± 2 years) were given 1000 mg of vitamin C or placebo over two visits in a randomized, double-blinded, within-subject design. Acute mental stress was induced using the Trier Social Stress Test (TSST). Saliva samples for cortisol determination and FMD measures were obtained at baseline, pre-TSST, and 30 and 90-min post-TSST. An additional saliva sample was obtained immediately post-TSST. Cardiovascular stress reactivity was characterized by changes in heart rate (HR) and mean arterial pressure (MAP). RESULTS: A significant stress response was elicited by the TSST in both conditions [MAP, HR, and salivary cortisol increased (p < 0.001)]. Overall FMD did not differ pre- vs. post-stress (time: p = 0.631) and there was no effect of vitamin C (condition: p = 0.792) (interaction between time and condition, p = 0.573). However, there was a correlation between cortisol reactivity and changes in FMD from pre- to post-stress in the placebo condition (r 2 = 0.66, p < 0.001) that was abolished in the vitamin C condition (r 2 = 0.02, p = 0.612). CONCLUSION: Acute mental stress did not impair endothelial function, and vitamin C disrupted the relationship between cortisol reactivity and changes in FMD post-stress. This suggests that acute mental stress does not universally impair endothelial function and that reactive oxygen species signaling may influence the interaction between FMD and stress responses.

SIRT3 gene expression but not SIRT3 subcellular localization is altered in response to fasting and exercise in human skeletal muscle.

NEW FINDINGS: What is the central question of this study? Evidence from cellular and animal models suggests that SIRT3 is involved in regulating aerobic ATP production. Thus, we investigated whether changes in fatty acid and oxidative metabolism known to accompany fasting and exercise occur in association with changes in SIRT3 mitochondrial localization and expression in human skeletal muscle. What is the main finding and its importance? We find that 48 h of fasting and acute endurance exercise decrease SIRT3 mRNA expression but do not alter SIRT3 mitochondrial localization despite marked increases in fatty acid oxidation. This suggests that SIRT3 activity is not regulated by changes in mitochondrial localization in response to cellular energy stress in human skeletal muscle. The present study examined SIRT3 expression and SIRT3 mitochondrial localization in response to acute exercise and short-term fasting in human skeletal muscle. Experiment 1 involved eight healthy men (age, 21.4 ± 2.8 years; peak O2 uptake, 47.1 ± 11.8 ml min(-1)  kg(-1) ) who performed a single bout of exercise at ∼55% of peak aerobic work rate for 1 h. Muscle biopsies were obtained at rest (Rest), immediately after exercise (EX-0) and 3 h postexercise (EX-3). Experiment 2 involved 10 healthy men (age, 22.0 ± 1.5 years; peak O2 uptake, 46.9 ± 6.0 ml min−1 kg−1) who underwent a 48 h fast, with muscle biopsies collected 1 h postprandial (Fed) and after 48 h of fasting (Fast). Mitochondrial respiration was measured using high-resolution respirometry in permeabilized muscle fibre bundles to assess substrate oxidation. Whole body fat oxidation increased after both exercise (Rest, 0.96 ± 0.32 kcal min(-1) ; Exercise, 5.66 ± 1.97 kcal min(-1) ; P < 0.001) and fasting (Fed, 0.87 ± 0.51 kcal min(-1) ; Fast, 1.30 ± 0.37 kcal min(-1) , P < 0.05). SIRT3 gene expression decreased (P < 0.05) after both exercise (-8%) and fasting (-19%); however, SIRT3 whole muscle protein content was unaltered after fasting. No changes were observed in SIRT3 mitochondrial localization following either exercise or fasting. Fasting also decreased the Vmax of glutamate [80 ± 43 versus 50 ± 21 pmol s(-1)  (mg dry weight)(-1) ; P < 0.05]. These findings suggest that SIRT3 does not appear to be regulated by changes in mitochondrial localization at the time points measured in the present study in response to cellular energy stress in human skeletal muscle.

Regulation of plasma agouti-related protein and its relationship with hunger in lean and obese men.

Agouti-related protein (AgRP) is an orexigenic (appetite stimulating) neuropeptide suggested to exert tonic control over long-term energy balance. While some have speculated AgRP is not involved in the episodic (i.e. meal to meal energy intake) control, acute decreases in plasma agouti-related protein (AgRP) following a meal have been observed in humans in a role consistent with episodic control for AgRP. Whether changes in plasma AgRP are associated with episodic, and/or tonic changes in appetite has yet to be directly examined. The present study examined the relationship between agouti-related protein (AgRP), leptin and the regulation of appetite following a 48-h fast and an acute meal challenge. Blood samples were obtained from young lean and obese men before and after a 48 h fast (lean n = 10; obese n = 7). Fasting resulted in an increase in AgRP and a decrease in leptin with these changes being greater in lean than obese. In addition, blood samples were obtained from lean men before and 1, 2, 3 and 4 h after a meal (n = 8). Following a meal, AgRP was reduced from 2 to 4 h, a change that was dissociated from both leptin and subjective measures of hunger and satiety. These results demonstrate that AgRP is not associated with changes in hunger or satiety, and can change without corresponding changes in leptin. This suggests that AgRP may not be involved in the episodic control of appetite and the release of AgRP may involve signals other than leptin.

Satellite cell activity, without expansion, after nonhypertrophic stimuli.

The purpose of the present studies was to determine the effect of various nonhypertrophic exercise stimuli on satellite cell (SC) pool activity in human skeletal muscle. Previously untrained men and women (men: 29 ± 9 yr and women: 29 ± 2 yr, n = 7 each) completed 6 wk of very low-volume high-intensity sprint interval training. In a separate study, recreationally active men (n = 16) and women (n = 3) completed 6 wk of either traditional moderate-intensity continuous exercise (n = 9, 21 ± 4 yr) or low-volume sprint interval training (n = 10, 21 ± 2 yr). Muscle biopsies were obtained from the vastus lateralis before and after training. The fiber type-specific SC response to training was determined, as was the activity of the SC pool using immunofluorescent microscopy of muscle cross sections. Training did not induce hypertrophy, as assessed by muscle cross-sectional area, nor did the SC pool expand in any group. However, there was an increase in the number of active SCs after each intervention. Specifically, the number of activated (Pax7(+)/MyoD(+), P ≤ 0.05) and differentiating (Pax7(-)/MyoD(+), P ≤ 0.05) SCs increased after each training intervention. Here, we report evidence of activated and cycling SCs that may or may not contribute to exercise-induced adaptations while the SC pool remains constant after three nonhypertrophic exercise training protocols.