Exercise and insulin resistance in PCOS: muscle insulin signalling and fibrosis.

OBJECTIVE: Mechanisms of insulin resistance in polycystic ovary syndrome (PCOS) remain ill defined, contributing to sub-optimal therapies. Recognising skeletal muscle plays a key role in glucose homeostasis we investigated early insulin signalling, its association with aberrant transforming growth factor ß (TGFß)-regulated tissue fibrosis. We also explored the impact of aerobic exercise on these molecular pathways. METHODS: A secondary analysis from a cross-sectional study was undertaken in women with (n = 30) or without (n = 29) PCOS across lean and overweight BMIs. A subset of participants with (n = 8) or without (n = 8) PCOS who were overweight completed 12 weeks of aerobic exercise training. Muscle was sampled before and 30 min into a euglycaemic-hyperinsulinaemic clamp pre and post training. RESULTS: We found reduced signalling in PCOS of mechanistic target of rapamycin (mTOR). Exercise training augmented but did not completely rescue this signalling defect in women with PCOS. Genes in the TGFß signalling network were upregulated in skeletal muscle in the overweight women with PCOS but were unresponsive to exercise training except for genes encoding LOX, collagen 1 and 3. CONCLUSIONS: We provide new insights into defects in early insulin signalling, tissue fibrosis, and hyperandrogenism in PCOS-specific insulin resistance in lean and overweight women. PCOS-specific insulin signalling defects were isolated to mTOR, while gene expression implicated TGFß ligand regulating a fibrosis in the PCOS-obesity synergy in insulin resistance and altered responses to exercise. Interestingly, there was little evidence for hyperandrogenism as a mechanism for insulin resistance.

Acute continuous moderate-intensity exercise, but not low-volume high-intensity interval exercise, attenuates postprandial suppression of circulating osteocalcin in young overweight and obese adults.

Bone remodeling markers (BRMs) are suppressed following the consumption of a meal. Our findings indicate that a single session of continuous moderate-intensity exercise, but not low-volume high-intensity interval exercise, performed 1 h after a meal attenuates the postprandial suppression of BRMs. INTRODUCTION: Acute exercise transiently increases BRMs including osteocalcin (tOC) and the undercarboxylated form of osteocalcin (ucOC), a hormone that is implicated in glucose regulation. The effects of acute exercise and exercise-intensity on postprandial levels of tOC and ucOC are unknown. METHODS: Twenty-seven adults that were overweight or obese (age 30 ± 1 years; BMI 30 ± 1 kg∙m-2; mean ± SEM) were randomly allocated to perform a single session of low-volume high-intensity interval exercise (LV-HIIE; nine females, five males) or continuous moderate-intensity exercise (CMIE; eightfemales, five males) 1 h after consumption of a standard breakfast. Serum tOC, ucOC, and ucOC/tOC were measured at baseline, 1 h, and 3 h after breakfast consumption on a rest day (no exercise) and the exercise day (exercise 1 h after breakfast). RESULTS: Compared to baseline, serum tOC and ucOC were suppressed 3 h after breakfast on the rest day (- 10 ± 1% and - 6 ± 2%, respectively; p < 0.05), whereas ucOC/tOC was elevated (2.5 ± 1%; p = 0.08). Compared to the rest day, CMIE attenuated the postprandial-induced suppression of tOC (rest day - 10 ± 2% versus CMIE - 5 ± 2%, p < 0.05) and ucOC (rest day - 6 ± 4% versus CMIE 11 ± 2%, p < 0.05), and increased postprandial ucOC/tOC (rest day 3 ± 2% versus CMIE 15 ± 1%, p < 0.05). In contrast, LV-HIIE did not alter postprandial tOC, ucOC, or ucOC/tOC (all p > 0.1). CONCLUSIONS: Acute CMIE, but not LV-HIIE, attenuates the postprandial-induced suppression of tOC and ucOC. CMIE may be an effective tool to control the circulating levels of BRMs following meal consumption in overweight/obese adults.

Informing Translation: The Accuracy of Information on Websites for Lifestyle Management of Polycystic Ovary Syndrome.

Lifestyle (diet, physical activity [PA], and/or behavioral) interventions are recommended for all women with polycystic ovary syndrome (PCOS) in international guidelines. The internet is a widely used health information resource. However, the accuracy of lifestyle information on PCOS websites is unknown and is reviewed here to inform translation of the international guideline on PCOS. An internet search was conducted with three search engines across different web browsers and countries. Accuracy was assessed through a checklist of 29 questions based on international guidelines for diet, PA, or weight management for the general population and for PCOS with higher scores indicating greater accuracy. Fifteen websites were eligible out of 72 (20%). The total accuracy score was 56 ± 13 (mean ± standard deviation; potential range: -29 to 87) comprising 23 ± 6 for diet (-11 to 33), 15 ± 5 for PA (-9 to 27), and 14 ± 3 for weight management (-8 to 24). A moderate proportion of websites provided general information on appropriate diet (40-80%) or weight management strategies (47-60%), but only 10 to 40% of websites provided information on core foods, discretionary foods, exercise quantity/intensity, energy deficits, or behavioral strategies. Limited websites on PCOS contain information on lifestyle management. The majority provided information on general diet, PA, and weight recommendations but less information on practical implementation of lifestyle change as an identified translation gap for the international guideline on PCOS.

Single-fiber expression and fiber-specific adaptability to short-term intense exercise training of Na+-K+-ATPase α- and ß-isoforms in human skeletal muscle.

The Na(+)-K(+)-ATPase (NKA) plays a key role in muscle excitability, but little is known in human skeletal muscle about fiber-type-specific differences in NKA isoform expression or adaptability. A vastus lateralis muscle biopsy was taken in 17 healthy young adults to contrast NKA isoform protein relative abundance between type I and IIa fibers. We further investigated muscle fiber-type-specific NKA adaptability in eight of these adults following 4-wk repeated-sprint exercise (RSE) training, comprising three sets of 5 × 4-s sprints, 3 days/wk. Single fibers were separated, and myosin heavy chain (I and IIa) and NKA (α1-3 and ß1-3) isoform abundance were determined via Western blotting. All six NKA isoforms were expressed in both type I and IIa fibers. No differences between fiber types were found for α1-, α2-, α3-, ß1-, or ß3-isoform abundances. The NKA ß2-isoform was 27% more abundant in type IIa than type I fibers (P < 0.05), with no other fiber-type-specific trends evident. RSE training increased ß1 in type IIa fibers (pretraining 0.70 ± 0.25, posttraining 0.84 ± 0.24 arbitrary units, 42%, P < 0.05). No training effects were found for other NKA isoforms. Thus human skeletal muscle expresses all six NKA isoforms and not in a fiber-type-specific manner; this points to their different functional roles in skeletal muscle cells. Detection of elevated NKA ß1 after RSE training demonstrates the sensitivity of the single-fiber Western blotting technique for fiber-type-specific intervention effects.

Futsal and continuous exercise induce similar changes in specific skeletal muscle signalling proteins.

Exercise elicits skeletal-muscle adaptations which are important for improved health outcomes. We compared the effects of a futsal game (FUT) and moderate-intensity continuous exercise (MOD), on the skeletal-muscle protein signalling responses in young, healthy individuals. 16 men undertook an incremental exercise test and a resting muscle biopsy performed >48 h apart. They were then randomly allocated to either FUT (n=12) consisting of 2 x 20 min halves, or MOD (n=8) consisting of a work-matched running bout performed at an intensity corresponding to the individual ventilatory threshold 1. Work matching was achieved by means of triaxial accelerometers. Immediately after FUT and MOD, participants underwent a second biopsy to assess exercise-induced changes in protein signalling. Total and phosphorylated protein abundance was assessed via western blotting. Both FUT and MOD altered signalling responses in skeletal muscle. FUT increased total ATF2 protein abundance (p=0.048) and phosphorylation (p=0.029), while no changes occurred with MOD. Both exercise regimes increased ACC phosphorylation (p=0.01) and returned a trend for increased p38MAPK phosphorylation. Futsal may be employed as an alternative to continuous exercise to elicit muscle adaptations which may be associated with improved health outcomes. As only FUT increased ATF2 activation, this protein might be a target of future investigation on exercise-induced signalling.

Effect of exercise training on insulin sensitivity, mitochondria and computed tomography muscle attenuation in overweight women with and without polycystic ovary syndrome.

AIMS/HYPOTHESIS: Polycystic ovary syndrome (PCOS) is an insulin resistant (IR) state. Increased skeletal muscle lipid content and impaired mitochondrial biogenesis have been implicated in the pathogenesis of IR. We investigated whether differences in these variables explain the IR of women affected by PCOS and whether improvements in IR with exercise are reflected by changes in these variables. METHODS: Sixteen PCOS and 13 non-PCOS overweight women were assessed, and eight PCOS and seven non-PCOS women were reassessed after 12 weeks of moderate and vigorous exercise training. Outcomes included insulin sensitivity (glucose infusion rate [GIR]), skeletal muscle gene expression and protein abundance, enzyme activity of selected mitochondrial components, and computed tomography (CT) attenuation-estimated muscle lipid. RESULTS: GIR was lower in women with PCOS versus those without (p = 0.01) and increased with exercise in both groups. Baseline CT muscle attenuation suggested a trend to less muscle lipid in PCOS, which increased with exercise training, with a difference in the change in muscle lipid (p = 0.01, age-corrected), compared with non-PCOS women. GIR correlated with PGC1A gene expression across the whole group; skeletal muscle expression of mitochondrial biogenesis markers was not different between groups at baseline, or after training. Neither lipid changes nor mitochondrial changes correlated with changes in GIR. CONCLUSIONS/INTERPRETATION: Differences in IR in women with and without PCOS were not explained by differences in skeletal muscle lipid or mitochondrial parameters. Improvements in IR with exercise were dissociated from mitochondrial parameters. CT muscle attenuation suggested a differential capacity of PCOS muscle to store lipid compared with non-PCOS. TRIAL REGISTRATION: Clinicaltrials.gov ISRCTN84763265. FUNDING: National Health & Medical Research Council (Grant number 606553), Monash University and The Jean Hailes Foundation.

Exercise decreases anti-müllerian hormone in anovulatory overweight women with polycystic ovary syndrome: a pilot study.

Polycystic ovary syndrome (PCOS) is a common condition in women associated with menstrual irregularity and anovulation. While obesity worsens and weight loss or exercise improves reproduction function in PCOS, the mechanism for this is unclear. The aim of this study was to examine the effect of exercise on ovarian hormones [anti-Müllerian hormone (AMH)] and menstrual and ovulatory function in women with and without PCOS. Overweight women with (n=7) and without (n=8) PCOS of comparable age, weight and BMI undertook a 12-week intensified endurance exercise training program (1 h 3 times/week) with no structured energy restriction. Primary outcomes were AMH, ovulation (weekly urinary pregnanediol) and menstrual regularity. Secondary outcomes were insulin resistance (euglycemic hyperinsulinemic clamp) and body composition (computed tomography and dual X-ray absorptiometry). Exercise decreased BMI, total and android fat mass and improved insulin sensitivity for all women. AMH was significantly higher in women with PCOS compared to controls before (p<0.001) and after exercise (p=0.001). There was a significant interaction between AMH changes with exercise and PCOS status (p=0.007) such that women without PCOS had no change in AMH (+1.4±5.2 pmol/l, p=0.48) while women with PCOS had a decrease in AMH (- 13.2±11.7 pmol/l, p=0.025). Exercise is associated with improvements in ovarian hormones in women with abnormal ovarian function. This suggests that mechanisms associated with ovarian dysfunction can be improved by exercise in PCOS.

Neuroendocrine and subjective responses to pharmacological challenge with citalopram: a controlled study in male and female ecstasy/MDMA users.

Despite evidence that +/-3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') causes persistent alterations to the serotonergic system of animals, evidence for long-term neurological effects of ecstasy/MDMA in humans remains equivocal. The current study assessed serotonin functioning of nine male and 11 female recreational ecstasy polydrug users by measuring neuroendocrine (prolactin, cortisol) responses to pharmacological challenge with the selective serotonin reuptake inhibitor citalopram, compared with nine male and five female cannabis polydrug users and 11 male and 11 female non-drug using controls. A single-blind, randomised, placebo-controlled design was used. Subjective responses, other substance use, mood, personality traits and demographic variables were measured to control for potentially confounding variables. There were no significant differences between ecstasy polydrug users, cannabis polydrug users and non-drug using controls in neuroendocrine or subjective responses to serotonergic challenge, and there were no sex by drug group interactions. There was no relationship between extent of ecstasy use and neuroendocrine functioning, alone or in combination with potential confounding variables. Subjective responses to the pharmacological challenge (nausea, tremor, dry mouth), novelty seeking and lifetime dose of alcohol were the only variables that contributed to one or more of the neuroendocrine outcome variables. These data do not support the premise that recreational ecstasy/MDMA use results in measurable impairment of serotonergic control of endocrine activity.

Adaptations to training in endurance cyclists: implications for performance.

Our present scientific knowledge of the effects of specific training interventions undertaken by professional cyclists on selected adaptive responses in skeletal muscle and their consequences for improving endurance performance is limited: sport scientists have found it difficult to persuade elite cyclists to experiment with their training regimens and access to muscle and blood samples from these athletes is sparse. Owing to the lack of scientific study we present a theoretical model of some of the major training-induced adaptations in skeletal muscle that are likely to determine performance capacity in elite cyclists. The model includes, but is not limited to, skeletal muscle morphology, acid-base status and fuel supply. A working premise is that the training-induced changes in skeletal muscle resulting from the high-volume, high-intensity training undertaken by elite cyclists is at least partially responsible for the observed improvements in performance. Using experimental data we provide evidence to support the model.

Effects of fat adaptation and carbohydrate restoration on prolonged endurance exercise.

We determined the effect of fat adaptation on metabolism and performance during 5 h of cycling in seven competitive athletes who consumed a standard carbohydrate (CHO) diet for 1 day and then either a high-CHO diet (11 g. kg(-1)x day(-1) CHO, 1 g x kg(-1) x day(-1) fat; HCHO) or an isoenergetic high-fat diet (2.6 g x kg(-1) x day(-1) CHO, 4.6 g x kg(-1) x day(-1) fat; fat-adapt) for 6 days. On day 8, subjects consumed a high-CHO diet and rested. On day 9, subjects consumed a preexercise meal and then cycled for 4 h at 65% peak O(2) uptake, followed by a 1-h time trial (TT). Compared with baseline, 6 days of fat-adapt reduced respiratory exchange ratio (RER) with cycling at 65% peak O(2) uptake [0.78 +/- 0.01 (SE) vs. 0.85 +/- 0.02; P < 0.05]. However, RER was restored by 1 day of high-CHO diet, preexercise meal, and CHO ingestion (0.88 +/- 0.01; P < 0.05). RER was higher after HCHO than fat-adapt (0.85 +/- 0.01, 0.89 +/- 0.01, and 0.93 +/- 0.01 for days 2, 8, and 9, respectively; P < 0.05). Fat oxidation during the 4-h ride was greater (171 +/- 32 vs. 119 +/- 38 g; P < 0.05) and CHO oxidation lower (597 +/- 41 vs. 719 +/- 46 g; P < 0.05) after fat-adapt. Power output was 11% higher during the TT after fat-adapt than after HCHO (312 +/- 15 vs. 279 +/- 20 W; P = 0.11). In conclusion, compared with a high-CHO diet, fat oxidation during exercise increased after fat-adapt and remained elevated above baseline even after 1 day of a high-CHO diet and increased CHO availability. However, this study failed to detect a significant benefit of fat adaptation to performance of a 1-h TT undertaken after 4 h of cycling.

Metabolic demands of intense aerobic interval training in competitive cyclists.

PURPOSE: To investigate the metabolic demands of a single session of intense aerobic interval training in highly trained competitive endurance cyclists. METHODS: Seven cyclists (peak O2 uptake [VO2 peak] 5.14 +/- 0.23 L x min(-1), mean +/-SD) performed 8 x 5 min work bouts at 86 +/- 2% of VO2 peak with 60-s recovery. Muscle biopsies were taken from the vastus lateralis immediately before and after the training session, whereas pulmonary gas exchange and venous blood were sampled at regular intervals throughout exercise. RESULTS: Muscle glycogen concentration decreased from 501 +/- 91 to 243 +/- 51 mmol x kg (-1) dry mass (P < 0.01). High rates of total carbohydrate oxidation were maintained throughout exercise (340 micromol.kg(-1).min(-1)), whereas fat oxidation increased from 16 +/- 8 during the first to 25 +/- 13 micromol x kg(-1) x min(-1) during the seventh work bout (P < 0.05). Blood lactate concentration remained between 5 and 6 mM throughout exercise, whereas muscle lactate increased from 6 +/- 1 at rest to 32 +/- 12 mmol x kg(-1) d.m. immediately after the training session (P < 0.01). Although muscle pH decreased from 7.09 +/- 0.06 at rest to 7.01 +/- 0.03 at the end of the session (P < 0.01), blood pH was similar after the first and seventh work bouts (7.34). Arterial oxygen saturation (% S(P)O2) fell to 95.6 +/- 1% during the first work bout and remained at 94% throughout exercise: the 60-s rest intervals were adequate to restore % S(P)O2) to 97%. CONCLUSION: Highly trained cyclists are able to sustain high steady state aerobic power outputs that are associated with high rates of glycogenolysis and total energy expenditure similar to those experienced during a 60-min competitive ride.

Enhancement of 2000-m rowing performance after caffeine ingestion.

PURPOSE: To investigate the effect of caffeine ingestion on short-term endurance performance in competitive rowers. METHODS: In this randomized double-blind crossover study, eight competitive oarsmen (peak oxygen uptake [VO2peak] 4.7+/-0.4 L x min(-1), mean +/- SD) performed three familiarization trials of a 2000-m rowing test on an air-braked ergometer, followed by three experimental trials at 3- to 7-d intervals, each 1 h after ingesting caffeine (6 or 9 mg x kg(-1) body mass) or placebo. Trials were preceded by a standardized warm-up (6 min at 225+/-39 W; 75+/-7.7% VO2peak). RESULTS: Urinary caffeine concentration was similar before ingestion (approximately 1 mg x L(-1)) but rose to 6.2+/-3.6 and 14.5+/-7.0 mg x L(-1) for the low and high caffeine doses, respectively. Plasma free fatty acid concentration before exercise was higher after caffeine ingestion (0.29+/-0.17 and 0.39+/-0.20 mM for 6 and 9 mg x kg(-1), respectively) than after placebo (0.13+/-0.05 mM). Respiratory exchange ratio during the warm-up was also substantially lower with caffeine (0.94+/-0.09 and 0.93+/-0.06 for the low and high dose) than with placebo (0.98+/-0.12). Subjects could not distinguish between treatments before or after the exercise test. Both doses of caffeine had a similar ergogenic effect relative to placebo: performance time decreased by a mean of 1.2% (95% likely range 0.4-1.9%); the corresponding increase in mean power was 2.7% (0.4-5.0%). Performance time showed some evidence of individual differences in the effect of caffeine (SD 0.9%; 95% likely range 1.5 to -0.9%). CONCLUSIONS: Ingestion of 6 or 9 mg x kg(-1) of caffeine produces a worthwhile enhancement of short-term endurance performance in a controlled laboratory setting.

Improved 2000-meter rowing performance in competitive oarswomen after caffeine ingestion.

Eight competitive oarswomen (age, 22 +/- 3 years; mass, 64.4 +/- 3.8 kg) performed three simulated 2,000-m time trials on a rowing ergometer. The trials, which were preceded by a 24-hour dietary and training control and 72 hours of caffeine abstinence, were conducted 1 hour after ingesting caffeine (6 or 9 mg á kg-1 body mass) or placebo. Plasma free fatty acid concentrations before exercise were higher with caffeine than placebo (0.67 +/- 0.34 vs. 0.72 +/- 0.36 vs. 0.30 +/- 0.10 mM for 6 and 9 mg á kg-1 caffeine and placebo, respectively; p <.05). Performance time improved 0.7% (95% confidence interval [CI] 0 to 1.5%) with 6 mg á kg-1 caffeine and 1. 3% (95% CI 0.5 to 2.0%) with 9 mg á kg-1 caffeine. The first 500 m of the 2,000 m was faster with the higher caffeine dose compared with placebo or the lower dose (1.53 +/- 0.52 vs.1.55 +/- 0.62 and 1. 56 +/- 0.43 min; p =.02). We concluded that caffeine produces a worthwhile enhancement of performance in a controlled laboratory setting, primarily by improving the first 500 m of a 2,000-m row.

Effects of different interval-training programs on cycling time-trial performance.

PURPOSE: We have investigated the effect of varying the intensity of interval training on 40-km time-trial performance in 20 male endurance cyclists (peak oxygen uptake 4.8+/-0.6 L x min(-1), mean +/- SD). METHODS: Cyclists performed a 25-kJ sprint test, an incremental test to determine peak aerobic power (PP) and a simulated 40-km time-trial on a Kingcycle ergometer. They were then randomly assigned to one of five types of interval-training session: 12x30 s at 175% PP, 12x60 s at 100% PP, 12x2 min at 90% PP, 8x4 min at 85% PP, or 4x8 min at 80% PP. Cyclists completed 6 sessions over 3 wk, in addition to their usual aerobic base training. All laboratory tests were then repeated. RESULTS: Performances in the time trial were highly reliable when controlled for training effects (coefficient of variation = 1.1%). The percent improvement in the time trial was modeled as a polynomial function of the rank order of the intensity of the training intervals, a procedure validated by simulation. The cubic trend was strong and statistically significant (overall correlation = 0.70, P = 0.005) and predicted greatest enhancement for the intervals performed at 85% PP (2.8%, 95% CI = 4.3-1.3%) and at 175% PP (2.4%, 95% CI = 4.0-0.7%). Intervals performed at 100% PP and 80% PP did not produce statistically significant enhancements of performance. Quadratic and linear trends were weak or insubstantial. CONCLUSIONS: Interval training with work bouts close to race-pace enhance 1-h endurance performance; work bouts at much higher intensity also appear to improve performance, possibly by a different mechanism.