Do Paralympic athletes suffer from brittle bones? Prevalence and risk factors of low bone mineral density in Paralympic athletes.

Background: Bone health may be a concern in Paralympic athletes, given the presence of multiple risk factors predisposing these athletes to low bone mineral density (BMD). Objective: We aimed to assess the prevalence of low BMD among Paralympic athletes participating in various sport disciplines, and to identify potential risk factors for low BMD. Methods: Seventy Paralympic athletes, of whom 51 % were wheelchair-dependent, were included in this cross-sectional study. BMD of the whole-body, lumbar spine, total hip, and femoral neck were assessed by dual-energy x-ray absorptiometry. Comparisons between groups were conducted by one-way ANOVA, and regression analyses were conducted to identify potential risk factors for low BMD. Results: The prevalence of low BMD (Z-score < -1.0) was highest at femoral neck (34 %), followed by total hip (31 %), whole-body (21 %), and lumbar spine (18 %). Wheelchair-dependent athletes had significantly lower BMD Z-scores compared to the non-wheelchair-dependent athletes at whole-body level (-0.5 ± 1.4 vs 0.2 ± 1.3; P = 0.04), total hip (-1.1 ± 1.2 vs 0.0 ± 1.1; P < 0.01), and femoral neck (-1.0 ± 1.3 vs -0.1 ± 1.2; P < 0.01). At the lumbar spine, low BMD was completely absent in wheelchair basketball and tennis players. Regression analyses identified body mass, wheelchair dependence, and type of sport, as the main risk factors for low BMD. Conclusions: In this cohort of Paralympic athletes, low BMD is mainly present at the hip, and to a lesser extent at the whole-body and lumbar spine. The most prominent risk factors for low BMD in Paralympic athletes are related to mechanical loading patterns, including wheelchair use, the type of sport, and body mass.

Transdermal oestradiol and exercise in androgen deprivation therapy (ESTRACISE): protocol.

OBJECTIVE: To report the protocol of a study evaluating the efficacy of transdermal oestradiol (E2) gel in reducing the adverse effects of androgen deprivation therapy (ADT), specifically on sexual function, and to assess the utility of E2 in combination with supervised exercise. STUDY DESIGN AND METHODS: The primary endpoint of this open-label Phase IIA randomized controlled trial is the efficacy of transdermal E2 gel. Secondary endpoints include: (i) the occurrence of ADT-induced adverse effects; (ii) the safety and tolerability of E2; (iii) the impact of E2 with or without exercise on physical, physiological, muscle, and systemic biomarkers; and (iv) quality of life. The trial will recruit high-risk PCa patients (n = 310) undergoing external beam radiation therapy with adjuvant subcutaneous ADT. Participants will be stratified and randomized in a 1:1 ratio to either the E2 + ADT arm or the ADT-only control arm. Additionally, a subset of patients (n = 120) will be randomized into a supervised exercise programme. RESULTS: The primary outcome is assessed according to the efficacy of E2 in mitigating the deterioration of Expanded Prostate Cancer Index Composite sexual function domain scores. Secondary outcomes are assessed according to the occurrence of ADT-induced adverse effects, safety and tolerability of E2, impact of E2 with or without exercise on physical performance, body composition, bone mineral density, muscle size, systematic biomarkers, and quality of life. CONCLUSION: The ESTRACISE study's innovative design can offer novel insights about the benefits of E2 gel, and the substudy can reinforce the benefits resistance training and deliver valuable new novel insights into the synergistic benefits of E2 gel and exercise, which are currently unknown. TRIAL REGISTRATION: The protocol has been registered in euclinicaltrials.eu (2023-504704-28-00) and in clinicaltrials.gov (NCT06271551).

Energy Requirements of Paralympic Athletes: Insights from the Doubly Labeled Water Approach.

PURPOSE: Advanced insight in energy requirements of Paralympic athletes is imperative for optimizing their nutritional counseling. Given the lack of accurate data on total daily energy expenditure (TDEE) of Paralympic athletes, this study aimed to assess energy expenditure and nutritional intake of a large cohort of Paralympic athletes, across different sports and disabilities. METHODS: In this cross-sectional study, 48 Dutch and Norwegian Paralympic athletes (19 male/29 female) with various disabilities, competing in Para cycling, wheelchair tennis, wheelchair basketball, Para Nordic skiing, and alpine skiing participated. TDEE was assessed by the gold standard doubly labeled water method over a 14-d period, resting metabolic rate by ventilated hood indirect calorimetry, energy intake by three unannounced 24-h dietary recalls, body composition by dual-energy x-ray absorptiometry, and exercise training duration by a training log. RESULTS: Mean TDEE was 2908 ± 797 kcal·d -1 , ranging from 2322 ± 340 kcal·d -1 for wheelchair basketball players to 3607 ± 1001 kcal·d -1 for Para cyclists. Regression analysis identified fat-free mass, exercise duration, and the presence of a spinal cord disorder as the primary predictors of TDEE, explaining up to 73% of the variance in TDEE. Athletes' energy intake (2363 ± 905 kcal·d -1 ) was below their TDEE, whereas their body mass remained constant, indicating underreporting. Carbohydrate intake (4.1 ± 1.9 g·kg -1 body mass) was low, even when considering underreporting, whereas protein intake (1.8 ± 0.6 g·kg -1 body mass) was relatively high. CONCLUSIONS: Paralympic athletes display moderate- to high-energy expenditure, varying across sports and individuals. Much of the variation in TDEE can be attributed to individual differences in fat-free mass and exercise duration. This study establishes the benchmarks for energy requirements of Paralympic athletes, serving as the foundation for future dietary guidelines within this population.

Physical Activity, Fitness, and Cardiovascular Disease Risk in Adolescent Childhood Cancer Survivors Compared to Controls: The Physical Activity in Childhood Cancer Survivors Study.

Purpose: Childhood cancer survivors have increased risk of cardiac late effects that can be potentially mitigated by physical activity and fitness. We aimed to (1) compare cardiovascular disease (CVD) risk between survivors and controls, and (2) examine whether the associations of moderate-to-vigorous physical activity (MVPA), cardiorespiratory fitness (CRF), and musculoskeletal fitness (MSF) with CVD risk factors differed between survivors and controls. Methods: Within the Physical Activity in Childhood Cancer Survivors (PACCS) study, we assessed CVD risk factors (android fat mass, systolic blood pressure [SBP], total cholesterol/high-density lipoprotein [HDL]-cholesterol, and glycosylated hemoglobin) in 157 childhood cancer survivors and 113 age- and sex-matched controls aged 9-18 years. We used multivariable mixed linear regression models to compare CVD risk factors between survivors and controls, and assess associations of MVPA, CRF, and MSF with CVD risk factors. Results: Compared with controls, survivors had more android fat mass (861 vs. 648 g, p = 0.001) and lower SBP (114 vs. 118 mmHg, p = 0.002). MVPA, CRF, and MSF were associated with lower levels of android fat mass and total cholesterol/HDL-cholesterol, and higher SBP in survivors. Associations of MVPA, CRF, and MSF with CVD risk factors were similar in survivors and controls (Pinteraction > 0.05), except the associations of CRF and MSF with android fat mass, which were stronger in survivors than in controls (Pinteraction ≤ 0.001). Conclusion: Owing to higher levels of android fat mass and its stronger association with physical fitness in childhood cancer survivors compared with controls, survivors should get targeted interventions to increase fitness to reduce future risk of CVD.

Effects of a 10-d Military Field Exercise on Body Composition, Physical Performance, and Muscle Cells in Men and Women.

PURPOSE: This study aimed to investigate the effects of a demanding military field exercise on physical performance, body composition, and muscle cellular outcomes in men and women. METHODS: Ten men (20.5 ± 0.5 yr) and 8 women (21.4 ± 1.4 yr) completed a 10-d field exercise consisting of extensive physical activity with food and sleep restriction. Acquisition of body composition, physical performance, blood, and muscle biopsies samples were done before and 1, 7, and 14 d after the exercise. RESULTS: There were no sex differences in the response to the exercise. Body mass was decreased with 5.6% ± 1.8% and fat mass with 31% ± 11% during the exercise. Both were still reduced after 14 d (2.5% ± 2.3%, P < 0.001, and 12.5% ± 7.7%, P < 0.001, respectively). Isometric leg strength did not change. Peak leg extension torque at 240°·s -1 and counter movement jump height were reduced with 4.6% ± 4.8% ( P = 0.012) and 6.7% ± 6.2% ( P < 0.001), respectively, and was still reduced after 14 d (4.3% ± 4.2%, P = 0.002, and 4.1% ± 4.7%, P = 0.030). No changes occurred in fiber CSA, fiber types, proteins involved in calcium handling, or HSP70. During the exercise, αB-crystallin levels decreased by 14% ± 19% ( P = 0.024) in the cytosolic fraction and staining intensity on muscle sections tended to increase (17% ± 25%, P = 0.076). MuRF1 levels in the cytosolic fraction tended to decrease (19% ± 35%) and increased with 85% ± 105% ( P = 0.003) in the cytoskeletal fraction 1 wk after the exercise. CONCLUSIONS: The field exercise resulted in reduced body mass and physical performance in both sexes. The ability to produce force at high contraction velocities and explosive strength was more affected than isometric strength, but this was not related to any changes in fiber type composition, fiber area, Ca 2+ handling, or fiber type-specific muscle damage.

DNA base oxidation in relation to TNM stages and chemotherapy treatment in colorectal cancer patients 2-9 months post-surgery.

Accumulation of DNA damage is a critical feature of genomic instability, which is a hallmark of various cancers. The enzyme-modified comet assay is a recognized method to detect specific DNA lesions at the level of individual cells. In this cross-sectional investigation, we explore possible links between clinicopathological and treatment related factors, nutritional status, physical activity and function, and DNA damage in a cohort of colorectal cancer (CRC) patients with non-metastatic disease. Levels of DNA damage in peripheral mononuclear blood cells (PBMCs) assessed 2-9 months post-surgery, were compared across tumour stage (localized (stage I-II) vs. regional (stage III) disease), localization (colon vs. rectosigmoid/rectum cancer), and adjuvant chemotherapy usage, with the last dosage administrated 2-191 days prior to sampling. Associations between DNA damage and indicators of nutritional status, physical activity and function were also explored. In PBMCs, DNA base oxidation was higher in patients diagnosed with regional compared with localized tumours (P = 0.03), but no difference was seen for DNA strand breaks (P > 0.05). Number of days since last chemotherapy dosage was negatively associated with DNA base oxidation (P < 0.01), and patients recently receiving chemotherapy (<15 days before blood collection) had higher levels of DNA base oxidation than those not receiving chemotherapy (P = 0.03). In the chemotherapy group, higher fat mass (in kg and %) as well as lower physical activity were associated with greater DNA base oxidation (P < 0.05). In conclusion, DNA base oxidation measured with the enzyme-modified comet assay varies according to tumour and lifestyle related factors in CRC patients treated for non-metastatic disease.

The development of physical characteristics in adolescent team sport athletes: A systematic review.

BACKGROUND: Physical development during adolescence is crucial for athletes in team sports, as it prepares them for the high sport demands at the senior level. While physical development in non-athletes are well-documented, a comprehensive understanding of adolescent athletes' development, including the potential effects of team sports participation and training load, is lacking. OBJECTIVES: The study aimed to investigate the development of physical characteristics in team sport athletes during adolescence (12-20 years) and explore the impact of training load. METHODS: A systematic search of the databases PubMed, SPORTDiscus and Web of Science were conducted combining keywords related to physical characteristics, youth athletes, team sport and study design. Criteria for inclusion were: (1) team sport athletes aged 12-20 years, (2) cross-sectional or longitudinal designs investigating physical characteristics, (3) comparisons across different age groups, (4) peer-reviewed original article, (5) written in English, and (6) available results from physical testing. Results were normalized and weighted based on sample size. RESULTS: 176 eligible articles were identified. The results showed consistent annual improvement in most physical characteristics from 12 to 16 years for both sexes (e.g., boys: lower body strength 14.3%; intermittent endurance 11%; countermovement jump height 6.7%; change of direction 2.8%; 30 m sprint 3.6%, and girls: lower body strength 9.4%; intermittent endurance 12.1%; countermovement jump 4.7%; change of direction 3.3%; 30 m sprint 1.9%). Only 4 studies investigated the effect of training load on physical development. CONCLUSIONS: Although both sexes consistently improved through adolescence, girls tended to have less pronounced physical development compared to boys, likely due to lower increase in lean mass and limb length. The existing evidence do not definitively establish whether team sports participation, compared to studies examining non-athletes, or training load have an additive effect on physical development during this period.

Correction: Effects of Aerobic Exercise on Cardiorespiratory Fitness, Cardiovascular Risk Factors, and Patient-Reported Outcomes in Long-Term Breast Cancer Survivors: Protocol for a Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/45244.].

Cold water immersion in recovery following a single bout resistance exercise suppresses mechanisms of miRNA nuclear export and maturation.

Cold water immersion (CWI) following intense exercise is a common athletic recovery practice. However, CWI impacts muscle adaptations to exercise training, with attenuated muscle hypertrophy and increased angiogenesis. Tissue temperature modulates the abundance of specific miRNA species and thus CWI may affect muscle adaptations via modulating miRNA expression following a bout of exercise. The current study focused on the regulatory mechanisms involved in cleavage and nuclear export of mature miRNA, including DROSHA, EXPORTIN-5, and DICER. Muscle biopsies were obtained from the vastus lateralis of young males (n = 9) at rest and at 2, 4, and 48 h of recovery from an acute bout of resistance exercise, followed by either 10 min of active recovery (ACT) at ambient temperature or CWI at 10°C. The abundance of key miRNA species in the regulation of intracellular anabolic signaling (miR-1 and miR-133a) and angiogenesis (miR-15a and miR-126) were measured, along with several gene targets implicated in satellite cell dynamics (NCAM and PAX7) and angiogenesis (VEGF and SPRED-1). When compared to ACT, CWI suppressed mRNA expression of DROSHA (24 h p = 0.025 and 48 h p = 0.017), EXPORTIN-5 (24 h p = 0.008), and DICER (24 h p = 0.0034). Of the analyzed miRNA species, miR-133a (24 h p < 0.001 and 48 h p = 0.007) and miR-126 (24 h p < 0.001 and 48 h p < 0.001) remained elevated at 24 h post-exercise in the CWI trial only. Potential gene targets of these miRNA, however, did not differ between trials. CWI may therefore impact miRNA abundance in skeletal muscle, although the precise physiological relevance needs further investigation.

Where Does Blood Flow Restriction Fit in the Toolbox of Athletic Development? A Narrative Review of the Proposed Mechanisms and Potential Applications.

Blood flow-restricted exercise is currently used as a low-intensity time-efficient approach to reap many of the benefits of typical high-intensity training. Evidence continues to lend support to the notion that even highly trained individuals, such as athletes, still benefit from this mode of training. Both resistance and endurance exercise may be combined with blood flow restriction to provide a spectrum of adaptations in skeletal muscle, spanning from myofibrillar to mitochondrial adjustments. Such diverse adaptations would benefit both muscular strength and endurance qualities concurrently, which are demanded in athletic performance, most notably in team sports. Moreover, recent work indicates that when traditional high-load resistance training is supplemented with low-load, blood flow-restricted exercise, either in the same session or as a separate training block in a periodised programme, a synergistic and complementary effect on training adaptations may occur. Transient reductions in mechanical loading of tissues afforded by low-load, blood flow-restricted exercise may also serve a purpose during de-loading, tapering or rehabilitation of musculoskeletal injury. This narrative review aims to expand on the current scientific and practical understanding of how blood flow restriction methods may be applied by coaches and practitioners to enhance current athletic development models.

Acute changes in antioxidants and oxidative stress to vigorous arm exercise: an intervention trial in persons with spinal cord injury and healthy controls.

STUDY DESIGN: Intervention trial. BACKGROUND: Literature remains unclear on possible health benefits and risks assosciated with high intensity exercise for persons with SCI. Elevated oxidative stress levels might influence their ability to exercise at high intensity. We investigated several biomarkers of oxidative stress and antioxidant defense at rest, during and after vigorous exercise among persons with chronic SCI. SETTING: Sunnaas Rehabilitation Hospital, Norway. METHODS: Six participants (five males) with chronic SCI (AIS A, injury level thoracic 2-8, >1 year postinjury) and six matched able-bodied controls performed two maximal arm-cranking tests, with one-three days in between. During the second exercise test, participants performed three bouts with four minutes arm cranking at high intensity (85-95% of peak heart rate (HRpeak)), before they reached maximal effort. Blood and urine biomarkers for oxidative stress and antioxidant levels were collected at six time points at the day of the second exercise test; baseline, at high intensity exercise, at maximal effort, at five, 30 and 60 min post-exercise, and 24 h post exercise. RESULTS: Participants with SCI had significant lower levels of creatinine (∆16 µmol/L, p = 0.03), α-carotene (∆0.14 nmol/L, p < 0.001) and ß-carotene (∆0.51 nmol/L, p = 0.001) at baseline compared to controls. Urine and blood biomarkers of oxidative stress and antioxidant levels showed similar response to vigorous exercise in the SCI and control group. CONCLUSIONS: SCI participants showed similar changes in redox status during high intensity exercise compared to matched able-bodied. SCI participants had lower levels of exogen antioxidants both before, during and after vigorous exercise.

Systolic myocardial function measured by echocardiographic speckle-tracking and peak oxygen consumption in pediatric childhood cancer survivors-a PACCS study.

Background: Cancer therapy-related cardiotoxicity is a major cause of cardiovascular morbidity in childhood cancer survivors. The aims of this study were to investigate systolic myocardial function and its association to cardiorespiratory fitness in pediatric childhood cancer survivors. Methods: In this sub-study of the international study "Physical Activity and fitness in Childhood Cancer Survivors" (PACCS), echocardiographic measures of left ventricular global longitudinal strain (LV-GLS) and right ventricular longitudinal strain (RV-LS) were measured in 128 childhood cancer survivors aged 9-18 years and in 23 age- and sex-matched controls. Cardiorespiratory fitness was measured as peak oxygen consumption achieved on treadmill and correlated to myocardial function. Results: Mean LV-GLS was reduced in the childhood cancer survivors compared to the controls, -19.7% [95% confidence interval (CI) -20.1% to -19.3%] vs. -21.3% (95% CI: -22.2% to -20.3%) (p = 0.004), however, mainly within normal range. Only 13% of the childhood cancer survivors had reduced LV longitudinal strain z-score. Mean RV-LS was similar in the childhood cancer survivors and the controls, -23.2% (95% CI: -23.7% to -22.6%) vs. -23.3% (95% CI: -24.6% to -22.0%) (p = 0.8). In the childhood cancer survivors, lower myocardial function was associated with lower peak oxygen consumption [correlation coefficient (r) = -0.3 for LV-GLS]. Higher doses of anthracyclines (r = 0.5 for LV-GLS and 0.2 for RV-LS) and increasing time after treatment (r = 0.3 for LV-GLS and 0.2 for RV-LS) were associated with lower myocardial function. Conclusions: Left ventricular function, but not right ventricular function, was reduced in pediatric childhood cancer survivors compared to controls, and a lower left ventricular myocardial function was associated with lower peak oxygen consumption. Furthermore, higher anthracycline doses and increasing time after treatment were associated with lower myocardial function, implying that long-term follow-up is important in this population at risk.

Effects of Aerobic Exercise on Cardiorespiratory Fitness, Cardiovascular Risk Factors, and Patient-Reported Outcomes in Long-Term Breast Cancer Survivors: Protocol for a Randomized Controlled Trial.

BACKGROUND: Anthracycline-based chemotherapy has been mainstay of adjuvant breast cancer therapy for decades. Although effective, anthracyclines place long-term breast cancer survivors at risk of late effects, such as reduced cardiorespiratory fitness and increased risk of cardiovascular disease. Previous research has shown beneficial effects of exercise training on cardiorespiratory fitness, but the effects of exercise on limiting factors for cardiorespiratory fitness, cardiovascular risk factors, and patient-reported outcomes in long-term survivors are less clear. Whether previous exposure to breast cancer therapy modulates the effects of exercise is also unknown. OBJECTIVE: The primary aim of the CAUSE (Cardiovascular Survivors Exercise) trial is to examine the effect of aerobic exercise on cardiorespiratory fitness in anthracycline-treated long-term breast cancer survivors. Secondary aims are to examine effects of exercise training on limiting factors for cardiorespiratory fitness, cardiovascular risk factors, and patient-reported outcomes, and to compare baseline values and effects of exercise training between similar-aged women with and those without prior breast cancer. A third aim is to examine the 24-month postintervention effects of aerobic exercise on primary and secondary outcomes. METHODS: The CAUSE trial is a 2-armed randomized controlled trial, where 140 long-term breast cancer survivors, 8-12 years post diagnosis, are assigned to a 5-month nonlinear aerobic exercise program with 3 weekly sessions or to standard care. Seventy similar-aged women with no history of cancer will undergo the same exercise program. Cardiorespiratory fitness measured as peak oxygen consumption (VO2peak), limiting factors for VO2peak (eg, cardiac function, pulmonary function, hemoglobin mass, blood volume, and skeletal muscle characteristics), cardiovascular risk factors (eg, hypertension, diabetes, dyslipidemia, obesity, physical activity level, and smoking status), and patient-reported outcomes (eg, body image, fatigue, mental health, and health-related quality of life) will be assessed at baseline, post intervention, and 24 months post intervention. RESULTS: A total of 209 patients were included from October 2020 to August 2022, and postintervention assessments were completed in January 2023. The 24-month follow-up will be completed in February 2025. CONCLUSIONS: The findings from the CAUSE trial will provide novel scientific understanding of the potential benefits of exercise training in long-term breast cancer survivors. TRIAL REGISTRATION: ClinicalTrials.gov NCT04307407; https://clinicaltrials.gov/ct2/show/NCT04307407. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45244.

Does inflammation markers or treatment type moderate exercise intensity effects on changes in muscle strength in cancer survivors participating in a 6-month combined resistance- and endurance exercise program? Results from the Phys-Can trial.

BACKGROUND: Resistance exercise has a beneficial impact on physical function for patients receiving oncological treatment. However, there is an inter-individual variation in the response to exercise and the tolerability to high-intensity exercise. Identifying potential moderating factors, such as inflammation and treatment type, for changes in muscle strength is important to improve the effectiveness of exercise programs. Therefore, we aimed to investigate if inflammation and type of oncological treatment moderate the effects of exercise intensity (high vs. low-moderate) on muscular strength changes in patients with breast (BRCA) or prostate cancer (PRCA). METHODS: Participants with BRCA (n = 286) and PRCA (n = 65) from the Physical training and Cancer study (Phys-Can) were included in the present study. Participants performed a combined resistance- and endurance exercise program during six months, at either high or low-moderate intensity. Separate regression models were estimated for each cancer type, with and without interaction terms. Moderators included in the models were treatment type (i.e., neo/adjuvant chemotherapy-yes/no for BRCA, adjuvant androgen deprivation therapy (ADT)-yes/no for PRCA)), and inflammation (interleukin 6 (IL6) and tumor necrosis factor-alpha (TNFα)) at follow-up. RESULTS: For BRCA, neither IL6 (b = 2.469, 95% CI [- 7.614, 12.552]) nor TNFα (b = 0.036, 95% CI [- 6.345, 6.418]) levels moderated the effect of exercise intensity on muscle strength change. The same was observed for chemotherapy treatment (b = 4.893, 95% CI [- 2.938, 12.724]). Similarly, for PRCA, the effect of exercise intensity on muscle strength change was not moderated by IL6 (b = - 1.423, 95% CI [- 17.894, 15.048]) and TNFα (b = - 1.905, 95% CI [- 8.542, 4.732]) levels, nor by ADT (b = - 0.180, 95% CI [- 11.201, 10.841]). CONCLUSIONS: The effect of exercise intensity on muscle strength is not moderated by TNFα, IL6, neo/adjuvant chemotherapy, or ADT, and therefore cannot explain any intra-variation of training response regarding exercise intensity (e.g., strength gain) for BRCA or PRCA in this setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02473003.

Aerobic exercise training resets the human skeletal muscle methylome 10 years after breast cancer treatment and survival.

Cancer survivors suffer impairments in skeletal muscle in terms of reduced mass and function. Interestingly, human skeletal muscle possesses an epigenetic memory of earlier stimuli, such as exercise. Long-term retention of epigenetic changes in skeletal muscle following cancer survival and/or exercise training has not yet been studied. We, therefore, investigated genome-wide DNA methylation (methylome) in skeletal muscle following a 5-month, 3/week aerobic-training intervention in breast cancer survivors 10-14 years after diagnosis and treatment. These results were compared to breast cancer survivors who remained untrained and to age-matched controls with no history of cancer, who undertook the same training intervention. Skeletal muscle biopsies were obtained from 23 females before(pre) and after(post) the 5-month training period. InfiniumEPIC 850K DNA methylation arrays and RT-PCR for gene expression were performed. The breast cancer survivors displayed a significant retention of increased DNA methylation (i.e., hypermethylation) at a larger number of differentially methylated positions (DMPs) compared with healthy age-matched controls pre training. Training in cancer survivors led to an exaggerated number of DMPs with a hypermethylated signature occurring at non-regulatory regions compared with training in healthy age-matched controls. However, the opposite occurred in important gene regulatory regions, where training in cancer survivors elicited a considerable reduction in methylation (i.e., hypomethylation) in 99% of the DMPs located in CpG islands within promoter regions. Importantly, training was able to reverse the hypermethylation identified in cancer survivors back toward a hypomethylated signature that was observed pre training in healthy age-matched controls at 300 (out of 881) of these island/promoter-associated CpGs. Pathway enrichment analysis identified training in cancer survivors evoked a predominantly hypomethylated signature in pathways associated with cell cycle, DNA replication/repair, transcription, translation, mTOR signaling, and the proteosome. Differentially methylated region (DMR) analysis also identified genes: BAG1, BTG2, CHP1, KIFC1, MKL2, MTR, PEX11B, POLD2, S100A6, SNORD104, and SPG7 as hypermethylated in breast cancer survivors, with training reversing these CpG island/promoter-associated DMRs toward a hypomethylated signature. Training also elicited a largely different epigenetic response in healthy individuals than that observed in cancer survivors, with very few overlapping changes. Only one gene, SIRT2, was identified as having altered methylation in cancer survivors at baseline and after training in both the cancer survivors and healthy controls. Overall, human skeletal muscle may retain a hypermethylated signature as long as 10-14 years after breast cancer treatment/survival. Five months of aerobic training reset the skeletal muscle methylome toward signatures identified in healthy age-matched individuals in gene regulatory regions.

Polyneuropathy in Adolescent Childhood Cancer Survivors: The PACCS Study.

BACKGROUND: Childhood cancer survivors (CCS) are at risk of polyneuropathy due to chemotherapy, but studies in young survivors are scarce and diagnosis is challenging. We aimed to study the presence of polyneuropathy and the possible effect of cumulative doses of chemotherapeutic agents in a representative group of adolescent survivors. METHODS: CCS aged nine to 18 years and age- and sex-matched controls were recruited from the cross-sectional Physical Activity and Fitness among Childhood Cancer Survivors (PACCS) study. CCS with various cancer diagnoses who had ended cancer treatment one year or more before study were included. Polyneuropathy was evaluated clinically and with nerve conduction studies (NCSs) in three motor and five sensory nerves. We used mixed-effects linear regression models to compare CCS and controls, and investigate possible associations between cumulative chemotherapy doses and NCS amplitudes. RESULTS: A total of 127 CCS and 87 controls were included, with 14% CCS having probable or confirmed polyneuropathy. NCS amplitudes were lower in survivors compared with controls in all nerves. The largest mean difference was 3.47 µV (95% confidence interval [CI], 2.18 to 4.75) in the tibial plantar medial sensory and 1.91 mV (95% CI, 0.78 to 3.04) in the tibial motor nerve. The cumulative dose of platinum derivatives was associated with lower tibial motor nerve amplitude (-0.20; 95% CI, -0.35 to -0.04 mV for 100 mg/m2 dose increase) but not in other nerves. We found no significant associations between vinca alkaloids cumulative dose and amplitudes. CONCLUSIONS: CCS without clinical signs or symptoms of polyneuropathy may have subtle nerve affection. The clinical long-term impact of this novel observation should be evaluated in larger, longitudinal studies.

Pre-treatment levels of inflammatory markers and chemotherapy completion rates in patients with early-stage breast cancer.

BACKGROUND: Chemotherapy efficacy is largely dependent on treatment adherence, defined by the relative dose intensity (RDI). Identification of new modifiable risk factors associated with low RDI might improve chemotherapy delivery. Here, we evaluated the association between low RDI and pre-chemotherapy factors, including patient- and treatment-related characteristics and markers of inflammation. METHODS: This exploratory analysis assessed data from 267 patients with early-stage breast cancer scheduled to undergo (neo-)adjuvant chemotherapy included in the Physical training and Cancer (Phys-Can) trial. The association between low RDI, defined as < 85%, patient-related (age, body mass index, co-morbid condition, body surface area) and treatment-related factors (cancer stage, receptor status, chemotherapy duration, chemotherapy dose, granulocyte colony-stimulating factor) was investigated. Analyses further included the association between RDI and pre-chemotherapy levels of interleukin (IL)-6, IL-8, IL-10, C-reactive protein (CRP) and Tumor Necrosis Factor-alpha (TNF-α) in 172 patients with available blood samples. RESULTS: An RDI of < 85% occurred in 31 patients (12%). Univariable analysis revealed a significant association with a chemotherapy duration above 20 weeks (p < 0.001), chemotherapy dose (p = 0.006), pre-chemotherapy IL-8 (OR 1.61; 95% CI (1.01; 2.58); p = 0.040) and TNF-α (OR 2.2 (1.17; 4.53); p = 0.019). In multivariable analyses, inflammatory cytokines were significant association with low RDI for IL-8 (OR: 1.65 [0.99; 2.69]; p = 0.044) and TNF-α (OR 2.95 [1.41; 7.19]; p = 0.007). CONCLUSIONS: This exploratory analysis highlights the association of pre-chemotherapy IL-8 and TNF-α with low RDI of chemotherapy for breast cancer. IL-8 and TNF-α may therefore potentially help to identify patients at risk for experiencing dose reductions. Clinical trial number NCT02473003 (registration: June 16, 2015).

Protocol for a randomised controlled trial to investigate the effects of vitamin K2 on recovery from muscle-damaging resistance exercise in young and older adults-the TAKEOVER study.

BACKGROUND: Regular participation in resistance exercise is known to have broad-ranging health benefits and for this reason is prominent in the current physical activity guidelines. Recovery after such exercise is important for several populations across the age range and nutritional strategies to enhance recovery and modulate post-exercise physiological processes are widely studied, yet effective strategies remain elusive. Vitamin K2 supplementation has emerged as a potential candidate, and the aim of the current study, therefore, is to test the hypothesis that vitamin K2 supplementation can accelerate recovery, via modulation of the underlying physiological processes, following a bout of resistance exercise in young and older adults. METHODS: The current study is a two-arm randomised controlled trial which will be conducted in 80 (40 young (≤40 years) and 40 older (≥65 years)) adults to compare post-exercise recovery in those supplemented with vitamin K2 or placebo for a 12-week period. The primary outcome is muscle strength with secondary outcomes including pain-free range of motion, functional abilities, surface electromyography (sEMG) and markers of inflammation and oxidative stress. DISCUSSION: Ethical approval has been granted by the College of Medical Veterinary and Life Sciences Ethical Committee at the University of Glasgow (Project No 200190189) and recruitment is ongoing. Study findings will be disseminated through a presentation at scientific conferences and in scientific journals. TRIAL REGISTRATION: ClinicialTrials.gov NCT04676958. Prospectively registered on 21 December 2020.

Effects of High and Low-To-Moderate Intensity Exercise During (Neo-) Adjuvant Chemotherapy on Muscle Cells, Cardiorespiratory Fitness, and Muscle Function in Women With Breast Cancer: Protocol for a Randomized Controlled Trial.

BACKGROUND: (Neo-)adjuvant chemotherapy for breast cancer is effective but has deleterious side effects on muscle tissue, resulting in reduced skeletal muscle mass, muscle function, and cardiorespiratory fitness. Various exercise regimens during cancer treatment have been shown to counteract some of these side effects. However, no study has compared the effect of high-intensity training versus low-to-moderate intensity training on muscle tissue cellular outcomes and physical function in patients with breast cancer during chemotherapy. OBJECTIVE: The aim of this substudy within the Physical Training in Cancer (Phys-Can) consortium is to evaluate and compare the effects of high and low-to-moderate intensity exercise on muscle cellular outcomes, muscle function, and cardiorespiratory fitness in women with breast cancer undergoing (neo-)adjuvant chemotherapy. We further aim to investigate if the effects of chemotherapy including taxanes on muscles will be different from those of taxane-free chemotherapy. METHODS: Eighty women recently diagnosed with breast cancer scheduled to start (neo-)adjuvant chemotherapy will be randomized to a combination of strength and endurance training, either at high intensity or at low-to-moderate intensity. Testing of muscle function and cardiorespiratory fitness and collection of muscle biopsies from the vastus lateralis muscle will be performed before the first cycle of chemotherapy (or after 1 week, when not possible) (T0), halfway through chemotherapy (T1), and after completion of chemotherapy (T2). It is estimated that approximately 50% of the participants will be willing to undergo muscle biopsies. To separate the effect of the treatment itself, a usual care group with no supervised training will also be included, and in this group, testing and collection of muscle biopsies will be performed at T0 and T2 only. RESULTS: This study is funded by Active Against Cancer (Aktiv mot kreft) (May 2013) and the Norwegian Cancer Society (December 2018). Inclusion started in December 2016 and the last participant is expected to be recruited in December 2022. As of June 2022, we enrolled 38 (19 with biopsies) participants to the high-intensity training group, 36 (19 with biopsies) participants to the low-to-moderate intensity training group, and 17 (16 with biopsies) participants to the usual care group. Data analyses will start in fall 2022. The first results are expected to be published in spring 2024. CONCLUSIONS: This study will generate new knowledge about the effects of different training intensities for women with breast cancer during chemotherapy treatment. It will give further insight into how chemotherapy affects the muscle tissue and how physical training at different intensities may counteract the treatment side effects in muscles. The results of this study will inform the development and refinement of exercise programs that are effective and compatible with the multidisciplinary management of breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT05218876; https://tinyurl.com/ysaj9dhm. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40811.

Heavy-load exercise in older adults activates vasculogenesis and has a stronger impact on muscle gene expression than in young adults.

BACKGROUND: A striking effect of old age is the involuntary loss of muscle mass and strength leading to sarcopenia and reduced physiological functions. However, effects of heavy-load exercise in older adults on diseases and functions as predicted by changes in muscle gene expression have been inadequately studied. METHODS: Thigh muscle global transcriptional activity (transcriptome) was analyzed in cohorts of older and younger adults before and after 12-13 weeks heavy-load strength exercise using Affymetrix microarrays. Three age groups, similarly trained, were compared: younger adults (age 24 ± 4 years), older adults of average age 70 years (Oslo cohort) and above 80 years (old BSU cohort). To increase statistical strength, one of the older cohorts was used for validation. Ingenuity Pathway analysis (IPA) was used to identify predicted biological effects of a gene set that changed expression after exercise, and Principal Component Analysis (PCA) was used to visualize differences in muscle gene expressen between cohorts and individual participants as well as overall changes upon exercise. RESULTS: Younger adults, showed few transcriptome changes, but a marked, significant impact was observed in persons of average age 70 years and even more so in persons above 80 years. The 249 transcripts positively or negatively altered in both cohorts of older adults (q-value < 0.1) were submitted to gene set enrichment analysis using IPA. The transcripts predicted increase in several aspects of "vascularization and muscle contractions", whereas functions associated with negative health effects were reduced, e.g., "Glucose metabolism disorder" and "Disorder of blood pressure". Several genes that changed expression after intervention were confirmed at the genome level by containing single nucleotide variants associated with handgrip strength and muscle expression levels, e.g., CYP4B1 (p = 9.2E-20), NOTCH4 (p = 9.7E-8), and FZD4 (p = 5.3E-7). PCA of the 249 genes indicated a differential pattern of muscle gene expression in young and elderly. However, after exercise the expression patterns in both young and old BSU cohorts were changed in the same direction for the vast majority of participants. CONCLUSIONS: The positive impact of heavy-load strength training on the transcriptome increased markedly with age. The identified molecular changes translate to improved vascularization and muscular strength, suggesting highly beneficial health effects for older adults.