Andrew J. R. Cochran

Muscle time under tension during resistance exercise stimulates differential muscle protein sub-fractional synthetic responses in men

Non‐technical summary  A single bout of resistance exercise stimulates the synthesis of new muscle proteins. Chronic performance of resistance exercise (i.e. weight training) is what makes your muscles grow bigger; a process known as hypertrophy. However, it is unknown if increasing the time that muscle is under tension will lead to greater increases in muscle protein synthesis. We report that leg extension exercise at 30% of the best effort (which is a load that is comparatively light), with a slow lifting movement (6 s up and 6 s down) performed to fatigue produces greater increases in rates of muscle protein synthesis than the same movement performed rapidly (1 s up and 1 s down). These results suggest that the time the muscle is under tension during exercise may be important in optimizing muscle growth; this understanding enables us to better prescribe exercise to those wishing to build bigger muscles and/or to prevent muscle loss that occurs with ageing or disease.

Matched work high-intensity interval and continuous running induce similar increases in PGC-1α mRNA, AMPK, p38, and p53 phosphorylation in human skeletal muscle

The aim of the present study was to test the hypothesis that acute high-intensity interval (HIT) running induces greater activation of signaling pathways associated with mitochondrial biogenesis compared with moderate-intensity continuous (CONT) running matched for work done. In a repeated-measures design, 10 active men performed two running protocols consisting of HIT [6 × 3-min at 90% maximal oxygen consumption (Vo(2max)) interspersed with 3-min recovery periods at 50% Vo(2max) with a 7-min warm-up and cool-down period at 70% Vo(2max)] or CONT (50-min continuous running at 70% Vo(2max)). Both protocols were matched, therefore, for average intensity, duration, and distance run. Muscle biopsies (vastus lateralis) were obtained preexercise, postexercise, and 3 h postexercise. Muscle glycogen decreased (P < 0.05) similarly in HIT and CONT (116 ± 11 vs. 111 ± 17 mmol/kg dry wt, respectively). Phosphorylation (P-) of p38MAPK(Thr180/Tyr182) (1.9 ± 0.1- vs. 1.5 ± 0.2-fold) and AMPK(Thr172) (1.5 ± 0.3- vs. 1.5 ± 0.1-fold) increased immediately postexercise (P < 0.05) in HIT and CONT, respectively, and returned to basal levels at 3 h postexercise. P-p53(Ser15) (HIT, 2.7 ± 0.8-fold; CONT, 2.1 ± 0.8-fold), PGC-1α mRNA (HIT, 4.2 ± 1.7-fold; CONT, 4.5 ± 0.9-fold) and HSP72 mRNA (HIT, 4.4 ± 2-fold; CONT, 3.5 ± 1-fold) all increased 3 h postexercise (P < 0.05) although neither parameter increased (P > 0.05) immediately postexercise. There was no difference between trials for any of the above signaling or gene expression responses (P > 0.05). We provide novel data by demonstrating that acute HIT and CONT running (when matched for average intensity, duration, and work done) induces similar activation of molecular signaling pathways associated with regulation of mitochondrial biogenesis. Furthermore, this is the first report of contraction-induced p53 phosphorylation in human skeletal muscle, thus highlighting an additional pathway by which exercise may initiate mitochondrial biogenesis.

Reduced carbohydrate availability enhances exercise-induced p53 signaling in human skeletal muscle: Implications for mitochondrial biogenesis

The mechanisms that regulate the enhanced skeletal muscle oxidative capacity observed when training with reduced carbohydrate (CHO) availability are currently unknown. The aim of the present study was to test the hypothesis that reduced CHO availability enhances p53 signaling and expression of genes associated with regulation of mitochondrial biogenesis and substrate utilization in human skeletal muscle. In a repeated-measures design, muscle biopsies (vastus lateralis) were obtained from eight active males before and after performing an acute bout of high-intensity interval running with either high (HIGH) or low CHO availability (LOW). Resting muscle glycogen (HIGH, 467 ± 19; LOW, 103 ± 9 mmol/kg dry wt) was greater in HIGH compared with LOW (P < 0.05). Phosphorylation (P-) of ACC(Ser79) (HIGH, 1.4 ± 0.4; LOW, 2.9 ± 0.9) and p53(Ser15) (HIGH, 0.9 ± 0.4; LOW, 2.6 ± 0.8) was higher in LOW immediately postexercise and 3 h postexercise, respectively (P < 0.05). Before and 3 h postexercise, mRNA content of pyruvate dehydrogenase kinase 4, mitochondrial transcription factor A, cytochrome-c oxidase IV, and PGC-1α were greater in LOW compared with HIGH (P < 0.05), whereas carnitine palmitoyltransferase-1 showed a trend toward significance (P = 0.09). However, only PGC-1α expression was increased by exercise (P < 0.05), where three-fold increases occurred independently of CHO availability. We conclude that the exercise-induced increase in p53 phosphorylation is enhanced in conditions of reduced CHO availability, which may be related to upstream signaling through AMPK. Given the emergence of p53 as a molecular regulator of mitochondrial biogenesis, such nutritional modulation of contraction-induced p53 activation has implications for both athletic and clinical populations.

Carbohydrate feeding during recovery alters the skeletal muscle metabolic response to repeated sessions of high-intensity interval exercise in humans

Exercise training under conditions of reduced carbohydrate (CHO) availability has been reported to augment gains in skeletal muscle oxidative capacity; however, the underlying mechanisms are unclear. We examined the effect of manipulating CHO intake on the acute metabolic response to high-intensity interval exercise, including signaling cascades linked to mitochondrial biogenesis. Ten men performed two trials in random order separated by >or=1 wk. Each trial consisted of a morning (AM) and afternoon (PM) training session (5 x 4 min cycling at approximately 90-95% of heart rate reserve) separated by 3 h of recovery during which subjects ingested a high-CHO drink (HI-HI) or nonenergetic placebo (HI-LO) before PM exercise. Biopsies (vastus lateralis) revealed that muscle phosphocreatine and ATP content were similar after AM exercise but decreased to a greater extent during PM exercise in HI-LO vs. HI-HI. Phosphorylation of p38 mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) increased approximately 4-fold and 2-fold, respectively, during AM exercise with no difference between conditions. After PM exercise, p38 MAPK phosphorylation was higher in HI-LO vs. HI-HI, whereas AMPK was not different between conditions. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) gene expression increased approximately 8-fold during recovery from AM exercise and remained elevated during PM exercise with no differences between conditions. Cytochrome oxidase subunit 4 (COXIV) mRNA was also elevated 3 h after AM exercise, with no difference between conditions. These data provide evidence that p38 MAPK is a nutrient-sensitive signaling molecule that could be involved in the altered skeletal muscle adaptive response reported after exercise training under conditions of restricted CHO intake, but further research is required to confirm this hypothesis.

Intermittent and continuous high‐intensity exercise training induce similar acute but different chronic muscle adaptations

What is the central question of this study? How important is the interval in high‐intensity interval training (HIIT)? What is the main finding and its importance? The intermittent nature of HIIT is important for maximizing skeletal muscle adaptations to this type of exercise, at least when a relatively small total volume of work is performed in an ‘all‐out’ manner. The protein signalling responses to an acute bout of HIIT were generally not predictive of training‐induced outcomes. Nonetheless, a single session of exercise lasting <10 min including warm‐up, performed three times per week for 6 weeks, was sufficient to improve maximal aerobic capacity.

β-Alanine Supplementation Does Not Augment the Skeletal Muscle Adaptive Response to 6 Weeks of Sprint Interval Training

Sprint interval training (SIT), repeated bouts of high-intensity exercise, improves skeletal muscle oxidative capacity and exercise performance. β-alanine (β-ALA) supplementation has been shown to enhance exercise performance, which led us to hypothesize that chronic β-ALA supplementation would augment work capacity during SIT and augment training-induced adaptations in skeletal muscle and performance. Twenty-four active but untrained men (23 ± 2 yr; VO2peak = 50 ± 6 mL · kg(-1) · min(-1)) ingested 3.2 g/day of β-ALA or a placebo (PLA) for a total of 10 weeks (n = 12 per group). Following 4 weeks of baseline supplementation, participants completed a 6-week SIT intervention. Each of 3 weekly sessions consisted of 4-6 Wingate tests, i.e., 30-s bouts of maximal cycling, interspersed with 4 min of recovery. Before and after the 6-week SIT program, participants completed a 250-kJ time trial and a repeated sprint test. Biopsies (v. lateralis) revealed that skeletal muscle carnosine content increased by 33% and 52%, respectively, after 4 and 10 weeks of β-ALA supplementation, but was unchanged in PLA. Total work performed during each training session was similar across treatments. SIT increased markers of mitochondrial content, including cytochome c oxidase (40%) and β-hydroxyacyl-CoA dehydrogenase maximal activities (19%), as well as VO2peak (9%), repeated-sprint capacity (5%), and 250-kJ time trial performance (13%), but there were no differences between treatments for any measure (p < .01, main effects for time; p > .05, interaction effects). The training stimulus may have overwhelmed any potential influence of β-ALA, or the supplementation protocol was insufficient to alter the variables to a detectable extent.

Regulating the regulators: the role of transcriptional regulatory proteins in the adaptive response to exercise in human skeletal muscle

It is well established that exercise training increases skeletal muscle mitochondrial content, and this adaptive response is linked with increased exercise tolerance and improved health. However, the mechanisms responsible for exercise-induced mitochondrial biogenesis are only beginning to be elucidated. Mitochondrial adaptations to exercise training in skeletal muscle are likely to be attributable to repeated transient increases in mRNA expression following each exercise session (see Perry et al. (2010) and references within). Over time, these successive ‘pulses’ of increased mRNA expression eventually lead to an accumulation of new muscle proteins, which constitute training adaptation and improve metabolic capacity. Data obtained from muscle-like cell lines and transgenic rodent models suggest a key role for transcriptional regulatory proteins in mediating the increase in mitochondrial content and the identification of those proteins responsible has become vital to advancing the field. Chief among these regulatory proteins is the transcriptional co-activator peroxisome proliferator-activated receptor γ co-activator (PGC)-1α, which has often been described as a ‘master regulator of mitochondrial biogenesis’. Overexpression of PGC-1α in skeletal muscle leads to many of the same adaptations as exercise training, such as an increase in mitochondrial content, improved fatigue resistance, and increased expression of proteins involved in lipid metabolism (e.g. Calvo et al. 2008). Therefore, it is generally accepted that transcriptional regulatory proteins, such as PGC-1α, are involved in mediating the adaptive increase in skeletal muscle mitochondrial content following exercise training. However, equally important to identifying those proteins responsible for regulating post-exercise elevations in mRNA expression is the characterization of the temporal relationship between and among transcriptional regulatory proteins and mitochondrial genes. Currently, there is a paucity of research examining the time course of the increase in transcriptional regulators in association with markers of mitochondrial content, especially in humans. A recent study published in The Journal of Physiology (Perry et al. 2010) comprehensively describes the time course for the increase in transcription factors and co-activators implicated in mitochondrial biogenesis along with markers of mitochondrial content, in human skeletal muscle, to shed light on this issue.