Transforming growth factor beta 1 impairs the transcriptomic response to contraction in myotubes from women with polycystic ovary syndrome

First published online 27 June 2022Polycystic ovary syndrome (PCOS) is characterised by a hormonal imbalance affecting the reproductive and metabolic health of reproductive-aged women. Exercise is recommended as a first-line therapy for women with PCOS to improve their overall health; however, women with PCOSare resistant to the metabolic benefits of exercise training. Here, we aimed to gain insight into the mechanisms responsible for such resistance to exercise in PCOS. We employed an in vitro approach with electrical pulse stimulation (EPS) of cultured skeletal muscle cells to explore whether myotubes from women with PCOS have an altered gene expression signature in response to contraction.Following EPS, 4719 genes were differentially expressed (false discovery rate<0.05) in myotubes from women with PCOS compared to 173 in healthy women. Both groups included genes involved in skeletal muscle contraction. We also determined the effect of two transforming growth factorβ(TGFβ) ligands that are elevated in plasma of women with PCOS, TGFβ1 and anti-Müllerianhormone (AMH), alone and on the EPS-induced response. While AMH (30 ng/ml) had no effect,TGFβ1 (5 ng/ml) induced the expression of extracellular matrix genes and impaired the exercise-like transcriptional signature in myotubes from women with and without PCOS in response to EPS by interfering with key processes related to muscle contraction, calcium transport and actin filament.Our findings suggest that while the fundamental gene expression responses of skeletal muscle to contraction is intact in PCOS, circulating factors like TGFβ1 may be responsible for the impaired adaptation to exercise in women with PCOS.Luke C. McIlvenna, Ali Altıntas, Rhiannon K. Patten, Andrew J. McAinch, Raymond J. Rodgers, Nigel K. Stepto, Romain Barrès, and Alba Moreno-Ass

Performance and physiological responses to repeated-sprint exercise: a novel multiple-set approach.

We investigated the acute and chronic responses to multiple sets of repeated-sprint exercise (RSE), focusing on changes in acceleration, intermittent running capacity and physiological responses. Ten healthy young adults (7 males, 3 females) performed an incremental test, a Yo-Yo intermittent recovery test level1 (Yo-Yo IR1), and one session of RSE. RSE comprised three sets of 5\ua0 7\ua04-s maximal sprints on a non-motorised treadmill, with 20\ua0s of passive recovery between repetitions and 4.5\ua0min of passive recovery between sets. After ten repeated-sprint training sessions, participants repeated all tests. During RSE, performance was determined by measuring acceleration, mean and peak power/velocity. Recovery heart rate (HR), HR variability, and finger-tip capillary lactate concentration ([Lac(-)]) were measured. Performance progressively decreased across the three sets of RSE, with the indices of repeated-sprint ability being impaired to a different extent before and after training. Training induced a significant increase (p\ua0<\ua00.05) in all indices of performance, particularly acceleration (21.9, 14.7 and 15.2\% during sets 1, 2 and 3, respectively). Training significantly increased Yo-Yo IR1 performance by 8\% and decreased \u394[Lac(-)]/work ratio (-15.2, -15.5, -9.4\% during sets 1, 2 and 3, respectively) and recovery HR during RSE. There were strong correlations between Yo-Yo IR1 performance and indices of RSE performance, especially acceleration post-training (r\ua0=\ua00.88, p\ua0=\ua00.004). Repeated-sprint training, comprising only 10\ua0min of exercise overall, effectively improved performance during multiple-set RSE. This exercise model better reflects team-sport activities than single-set RSE. The rapid training-induced improvement in acceleration, quantified here for the first time, has wide applications for professional and recreational sport activities

Key signalling pathways underlying the aetiology of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine condition characterised by a range of reproductive, endocrine, metabolic and psychological abnormalities. Reports estimate that around 10% of women of reproductive age are affected by PCOS, representing a significant prevalence worldwide, which poses a high economic health burden. As the origin of PCOS remains largely unknown, there is neither a cure nor mechanism-based treatments leaving patient management suboptimal and focused solely on symptomatic treatment. However, if the underlying mechanisms underpinning the development of PCOS were uncovered then this would pave the way for the development of new interventions for PCOS. Recently, there have been significant advances in our understanding of the underlying pathways likely involved in PCOS pathogenesis. Key insights include the potential involvement of androgens, insulin, antiMüllerian hormone and transforming growth factor beta in the development of PCOS. This review will summarise the significant scientific discoveries on these factors that have enhanced our knowledge of the mechanisms involved in the development of PCOS and discuss the impact these insights may have in shaping the future development of effective strategies for women with PCOS.Kirsty A Walters, Alba Moreno-Asso, Nigel K Stepto, Michael W Pankhurst, Valentina Rodriguez Paris, and Raymond J Rodger

Vitamin D in polycystic ovary syndrome: Relationship to obesity and insulin resistance

Scope: Polycystic ovary syndrome (PCOS) is underpinned by insulin resistance (IR). In PCOS, the relationships between vitamin D, adiposity, and IR are unclear. We aim to explore these relationships in lean and overweight women with PCOS. Methods and results: This is a cross-sectional study conducted in a tertiary medical center. Participants included 42 women with PCOS and 34 controls without PCOS. Vitamin D and metabolic markers were measured. Detailed body composition and gold standard hyperinsulinemic euglycemic clamps were performed. The main outcome measures were plasma levels of vitamin D, adiposity measures, and glucose infusion rate. Vitamin D levels were lower in overweight women with PCOS compared with overweight controls (31.6 and 46.1 nmol/L, respectively, p = 0.01). Vitamin D was not associated with IR after adjustment for confounders; however, there was a significant interaction between PCOS and percentage body fat. Further analysis by PCOS status revealed that vitamin D was associated with IR in the PCOS group (β coefficient 2.1, 95% CI 0.2–4.0, p = 0.03), but not in the non-PCOS group. Conclusion: Vitamin D is associated with IR in women with PCOS, but not in controls. Large intervention studies are needed to determine if vitamin D supplementation can improve IR in PCOS.Anju E. Joham, Helena J. Teede, Samantha Cassar, Nigel K. Stepto, Boyd J. Strauss, Cheryce L. Harrison, Jacqueline Boyle and Barbora de Courte

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.Thaw Htet, S. Cassar, Jacqueline A. Boyle, Millicent Kuczynska-Burggraf, Melanie Gibson-Helm, Wei-Ling Chiu, N.K. Stepto, Lisa J. Mora

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\u2009h apart. They were then randomly allocated to either FUT (n=12) consisting of 2\u2009x\u200920\u2009min 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

High-intensity training elicits greater improvements in cardio-metabolic and reproductive outcomes than moderate-intensity training in women with polycystic ovary syndrome: a randomized clinical trial

Advance Access Publication on March 23, 2022STUDY QUESTION: Does 12 weeks of high-intensity interval training (HIIT) result in greater improvements in cardio-metabolic and reproductive outcomes compared to standard moderate-intensity continuous training (MICT) in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: HIIT offers greater improvements in aerobic capacity, insulin sensitivity and menstrual cyclicity, and larger reductions in hyperandrogenism compared to MICT. WHAT IS KNOWN ALREADY Exercise training is recognized to improve clinical outcomes in women with PCOS, but little is known about whether HIIT results in greater health outcomes compared to standard MICT. STUDY DESIGN, SIZE, DURATION: This was a two-armed randomized clinical trial enrolling a total of 29 overweight women with PCOS between May 2016 and November 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS aged 18–45 years were randomly assigned to 12 weeks of either MICT (60–75% peak heart rate, N = 14) or HIIT (>90% peak heart rate, N = 15), each completed three times per week. The primary clinical outcomes were aerobic capacity (VO2peak) and insulin sensitivity (euglycaemic–hyperinsulinaemic clamp). Secondary outcomes included hormonal profiles, menstrual cyclicity and body composition. MAIN RESULTS AND THE ROLE OF CHANCE Both HIIT and MICT improved VO2peak (HIIT; Δ 5.8 ± 2.6 ml/kg/min, P < 0.001 and MICT; Δ 3.2 ± 2 ml/kg/min, P < 0.001), however, the HIIT group had a greater improvement in aerobic capacity compared to MICT (β = 2.73 ml/kg/min, P = 0.015). HIIT increased the insulin sensitivity index compared to baseline (Δ 2.3 ± 4.4 AU, P = 0.007) and MICT (β = 0.36 AU, P = 0.030), and caused higher increases in sex hormone-binding globulin compared to MICT (β = 0.25 nmol/l, P = 0.002). HIIT participants were 7.8 times more likely to report improved menstrual cyclicity than those in the MICT group (odds ratio 7.8, P = 0.04). LIMITATIONS, REASONS FOR CAUTION This study has a small sample size and the findings of the effect of the exercise interventions are limited to overweight reproductive-aged women, who do not have any co-existing co-morbidities that require medication. WIDER IMPLICATIONS OF THE FINDINGS Exercise, regardless of intensity, has clear health benefits for women with PCOS. HIIT appears to be a more beneficial strategy and should be considered for promoting health and reducing cardio-metabolic risk in overweight women with PCOS.Rhiannon K Patten, Luke C McIlvenna, Itamar Levinger, Andrew P Garnham, Soulmaz Shorakae, Alexandra G Parker, Andrew J McAinch, Raymond J Rodgers, Danielle Hiam, Alba Moreno-Asso, Nigel K Stept