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Background: Women with breast cancer undergoing chemotherapy suffer from a range of detrimental disease and treatment related side-effects. Exercise has shown to be able to counter some of these side-effects and improve physical function as well as quality of life. The primary aim of the study is to investigate and compare the effects of two different exercise regimens on the primary outcome cancer-related fatigue and the secondary outcomes muscle strength, function and structure, cardiovascular fitness, systemic inflammation, skeletal muscle gene activity, health related quality of life, pain, disease and treatment-related symptoms in women with breast cancer receiving chemotherapy. The second aim is to examine if any effects are sustained 1, 2, and 5 years following the completion of the intervention and to monitor return to work, recurrence and survival. The third aim of the study is to examine the effect of attendance and adherence rates on the effects of the exercise programme.Methods: This study is a randomised controlled trial including 240 women with breast cancer receiving chemotherapy in Stockholm, Sweden. The participants are randomly allocated to either: group 1: Aerobic training, group 2: Combined resistance and aerobic training, or group 3: usual care (control group). During the 5-year follow-up period, participants in the exercise groups will receive a physical activity prescription. Measurements for endpoints will take place at baseline, after 16 weeks (end of intervention) as well as after 1, 2 and 5 years.Discussion: This randomised controlled trial will generate substantial information regarding the effects of different types of exercise on the health of patients with breast cancer undergoing chemotherapy. We expect that dissemination of the knowledge gained from this study will contribute to developing effective long term strategies to improve the physical and psychosocial health of breast cancer survivors.Trial Registration: OptiTrain - Optimal Training Women with Breast Cancer (OptiTrain), NCT02522260 ; Registration: June 9, 2015, Last updated version Feb 29, 2016. Retrospectively registered. [ABSTRACT FROM AUTHOR]

Introduction A truncated PGC-1 α splice variant ( PGC-1 α4) has been implicated in the regulation of resistance exercise ( RE)-induced muscle hypertrophy, and basal expression levels said to be augmented in response to concurrent aerobic ( AE) and RE training. Aim The current study investigated human muscle truncated and non-truncated PGC-1 α transcripts in response to both acute and chronic RE, and with or without preceding AE ( AE+ RE). Methods Ten men performed 5 weeks of unilateral AE+ RE and RE training. Before (untrained) and after (trained) this intervention, PGC-1 α transcripts were assessed in vastus lateralis muscle biopsies obtained before and 3 h after acute RE, with or without preceding AE. Additionally, samples were collected 72 h after the last exercise bout of the training programme. Results The truncated splice variant increased ( P < 0.05) its expression after acute exercise regardless of mode. However, the expression was greater ( P < 0.05) after AE+ RE than RE. Other PGC-1 α transcripts showed similar response. Truncated transcripts originated from both the alternative and proximal promoter, and AE+ RE increased PGC-1 α expression from both promoter sites. RE induced transcripts from the alternative promoter only. PGC-1 α expressions after acute exercise were comparable across isoforms in both untrained and trained muscle. Steady-state levels of isoforms were unchanged after 5-week training ( P > 0.05). Exercise-induced expression of PGC-1 α variants did not correlate with changes in muscle size or strength ( P > 0.05). Conclusion Our results do not support the view that truncated PGC-1 α coordinates exercise-induced hypertrophy in human skeletal muscle. Rather, all PGC-1 α isoforms appear to be regulated transiently in response to acute exercise and regardless of mode. [ABSTRACT FROM AUTHOR]

The present study investigated whether exercise induces the expression of PGC-1α splice variants in human skeletal muscle and the possible influence of metabolic perturbation on this response. The subjects exercised one leg for 45 min with restricted blood flow (R-leg), followed by 45 min of exercise using the other leg at the same absolute workload but with normal blood flow (NR-leg). This ischemic model (R-leg) has been shown previously to induce a greater metabolic perturbation and enhance the expression of PGC-1α beyond that observed in the NR-leg. Cultured human myotubes were used to test suggested exercise-induced regulatory stimuli of PGC-1α. We showed, for the first time, that transcripts from both the canonical promoter (PGC-1α-a) and the proposed upstream-located promoter (PGC-1α-b) are present in human skeletal muscle. Both transcripts were upregulated after exercise in the R-leg, but the fold change increase of PGC-1α-b was much greater than that of PGC-1a-a. No differences were observed between the two conditions regarding the marker for calcineurin activation, MCIP1, or p38 phosphorylation. AMPK phosphorylation increased to a greater extent in the R-leg, and AICAR stimulation of cultured human myotubes induced the expression of PGC-1α-a and PGC-1α-b. AICAR combined with norepinephrine yielded an additive effect on the PGC-1α-b expression only. Our results indicate clearly that exercise can activate an upstream promoter in humans and support AMPK as a major regulator of transcripts from the canonical PGC-1α promoter and the involvement of β-adrenergic stimulation in combination with AMPK in the regulation of PGC-1α-b. [ABSTRACT FROM AUTHOR]

Eleven subjects performed one-legged exercise four times per week for 5 wk. The subjects exercised one leg for 45 mm with restricted blood flow (R leg), followed by exercise with the other leg at the same absolute workload with unrestricted blood flow (UR leg). mRNA and protein expression were measured in biopsies from the vastus lateralis muscle obtained at rest before the training period, after 10 days, and after 5 wk of training, as well as 120 mm after the first and last exercise bouts. Basal Ang-2 and Tie- 1 mRNA levels increased in both legs with training. The Ang-2-to-Ang- 1 ratio increased to a greater extent in the R leg. The changes in Ang-2 mRNA were followed by similar changes at the protein level. In the R leg, VEGF-A mRNA expression responded transiently after acute exercise both before and after the 5-wk training program. Over the course of the exercise program, there was a concurrent increase in basal VEGF-A protein and VEGFR-2 mRNA in the R leg. Ki-67 mRNA showed a greater increase in the R leg and the protein was localized to the endothelial cells. In summary, the increased translation of VEGF-A is suggested to be caused by the short mRNA burst induced by each exercise bout. The concurrent increase in the Ang-2-to-Ang- 1 ratio and the VEGF-expression combined with the higher level of Ki-67 mRNA in the R leg indicate that changes in these systems are of importance also in nonpathological angiogenic condition such as voluntary exercise in humans. It further establish that hypoxialischemia-related metabolic perturbation is likely to be involved as stimuli in this process in human skeletal muscle. [ABSTRACT FROM AUTHOR]

Aims: Studies from genetically modified animals have been instrumental in highlighting genes and their products involved in the regulation of muscle fibre type and oxidative phenotypes; however, evidence in humans is limited. Our aim was therefore to investigate expression of those genes implicated in the regulation of oxidative fibre phenotypes in humans. Methods: Using quantitative polymerase chain reaction we determined mRNA expression of selected genes in skeletal muscle from three different groups, displaying physiological and pathological variations in muscle fibre type, activity and skeletal muscle metabolism respectively: (i) elite athletes (cyclists), with an increased proportion of type I slow twitch, oxidative fibres, (ii) normally active subjects with an average fibre type distribution, and (iii) spinal cord-injured subjects with a low proportion of type I fibres. Results: Skeletal muscle mRNA expression of calcineurin A α and A β, peroxisome proliferator-activated receptor (PPAR)- α and - δ, and PPAR gamma coactivator (PGC)-1 α and -1 β was determined. Calcineurin A α and calcineurin A β mRNA expression was similar between groups. In contrast, mRNA expression of PPAR α, PPAR δ, PGC-1 α and -1 β was increased in athletes, when compared with normally active subjects. Furthermore, mRNA expression of PPAR α, PPAR δ, PGC-1 α and -1 β was reduced in spinal cord-injured subjects. Additionally, PPAR α, PPAR δ and PGC-1 α correlated with oxidative fibre content. Conclusion: Skeletal muscle mRNA expression of PPAR α, PPAR δ, PGC-1 α and -1 β reflects differences in type I muscle fibres associated with pathologically and physiologically induced skeletal muscle fibre type differences. [ABSTRACT FROM AUTHOR]

A detailed understanding of molecular responses to a hypertrophic stimulus in skeletal muscle leads to therapeutic advances aimed at promoting muscle mass. To decode the molecular factors regulating skeletal muscle mass, we utilized a 24-h time course of human muscle biopsies after a bout of resistance exercise. Our findings indicate: (1) the DNA methylome response at 30 min corresponds to upregulated genes at 3 h, (2) a burst of translation- and transcription-initiation factor-coding transcripts occurs between 3 and 8 h, (3) changes to global protein-coding gene expression peaks at 8 h, (4) ribosome-related genes dominate the mRNA landscape between 8 and 24 h, (5) methylation-regulated MYC is a highly influential transcription factor throughout recovery. To test whether MYC is sufficient for hypertrophy, we periodically pulse MYC in skeletal muscle over 4 weeks. Transient MYC increases muscle mass and fiber size in the soleus of adult mice. We present a temporally resolved resource for understanding molecular adaptations to resistance exercise in muscle ( http://data.myoanalytics.com ) and suggest that controlled MYC doses influence the exercise-related hypertrophic transcriptional landscape., Competing Interests: Disclosure and competing interests statement. YW is the founder of MyoAnalytics LLC. The authors have no other conflicts to declare., (© 2024. The Author(s).)

Background: Physical activity is well known for its multiple health benefits and although the knowledge of the underlying molecular mechanisms is increasing, our understanding of the role of epigenetics in long-term training adaptation remains incomplete. In this intervention study, we included individuals with a history of > 15 years of regular endurance or resistance training compared to age-matched untrained controls performing endurance or resistance exercise. We examined skeletal muscle DNA methylation of genes involved in key adaptation processes, including myogenesis, gene regulation, angiogenesis and metabolism., Results: A greater number of differentially methylated regions and differentially expressed genes were identified when comparing the endurance group with the control group than in the comparison between the strength group and the control group at baseline. Although the cellular composition of skeletal muscle samples was generally consistent across groups, variations were observed in the distribution of muscle fiber types. Slow-twitch fiber type genes MYH7 and MYL3 exhibited lower promoter methylation and elevated expression in endurance-trained athletes, while the same group showed higher methylation in transcription factors such as FOXO3, CREB5, and PGC-1α. The baseline DNA methylation state of those genes was associated with the transcriptional response to an acute bout of exercise. Acute exercise altered very few of the investigated CpG sites., Conclusions: Endurance- compared to resistance-trained athletes and untrained individuals demonstrated a different DNA methylation signature of selected skeletal muscle genes, which may influence transcriptional dynamics following a bout of acute exercise. Skeletal muscle fiber type distribution is associated with methylation of fiber type specific genes. Our results suggest that the baseline DNA methylation landscape in skeletal muscle influences the transcription of regulatory genes in response to an acute exercise bout., (© 2024. The Author(s).)

Background: The menstrual cycle and its impact on training and performance are of growing interest. However, evidence is lacking whether periodized exercise based on the menstrual cycle is beneficial. The primary purpose of this proposed randomized, controlled trial, the IMPACT study, is to evaluate the effect of exercise periodization during different phases of the menstrual cycle, i.e., comparing follicular phase-based and luteal phase-based training with regular training during the menstrual cycle on physical performance in well-trained women., Methods: Healthy, well-trained, eumenorrheic women between 18 and 35 years (n = 120) will be recruited and first assessed for physical performance during a run-in menstrual cycle at different cycle phases and then randomized to three different interventions: follicular phase-based training, luteal phase-based training, or regular training during three menstrual cycles. The training intervention will consist of high-intensity spinning classes followed by strength training. The menstrual cycle phases will be determined by serum hormone analysis throughout the intervention period. Assessment of aerobic performance (primary outcome) and muscle strength, body composition, and blood markers will be performed at baseline and at the end of the intervention., Discussion: With a robust methodology, this study has the potential to provide evidence of the differential effects of exercise periodization during different phases of the menstrual cycle in female athletes., Trial Registration: ClinicalTrials.gov NCT05697263 . Registered on 25 January 2023., (© 2024. The Author(s).)

Objectives: The aim of the study were to (1) investigate what physical and physiological parameters are most important for Frame Running capacity, a parasport for individuals with ambulatory difficulties, and (2) determine whether Frame Running capacity can be predicted in athletes with cerebral palsy., Design: Athletes with cerebral palsy ( N = 62, Gross Motor Classification System I-V; 2/26/11/21/2) completed a 6-min Frame Running test. Before the 6-min Frame Running test, muscle thickness, passive range of motion (hip, knee, ankle), selective motor control, and spasticity (hip, knee, ankle) were measured in both legs. In total, 54 variables per individual were included. Data were analyzed using correlations, principal component analysis, orthogonal partial least square regression, and variable importance in projection analysis., Results: The mean 6-min Frame Running test distance was 789 ± 335 m and decreased with motor function severity. The orthogonal partial least square analysis revealed a modest degree of covariance in the variables analyzed and that the variance in the 6-min Frame Running test distance could be predicted with 75% accuracy based on all the variables measured. Variable importance in projection analysis indicated hip and knee extensor spasticity (negative effect), and muscle thickness (positive effect) arose as the most important factors contributing to Frame Running capacity., Conclusions: These results are an important resource to enable optimization of training regimes to improve Frame Running capacity and contribute to evidence-based and fair classification for this parasport., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In this study, the properties of circulating extracellular vesicles (EVs) were examined in cerebral palsy (CP) and typically developed (TD) individuals at rest and after aerobic exercise, focusing on the size, concentration, and microRNA cargo of EVs. Nine adult individuals with CP performed a single exercise bout consisting of 45 min of Frame Running, and TD participants completed either 45 min of cycling ( n = 10; TD EX) or were enrolled as controls with no exercise ( n = 10; TD CON). Blood was drawn before and 30 min after exercise and analyzed for EV concentration, size, and microRNA content. The size of EVs was similar in CP vs. TD, and exercise had no effect. Individuals with CP had an overall lower concentration (∼25%, p < 0.05) of EVs. At baseline, let-7a, let-7b and let-7e were downregulated in individuals with CP compared to TD ( p < 0.05), while miR-100 expression was higher, and miR-877 and miR-4433 lower in CP compared to TD after exercise ( p < 0.05). Interestingly, miR-486 was upregulated ∼2-fold in the EVs of CP vs. TD both at baseline and after exercise. We then performed an in silico analysis of miR-486 targets and identified the satellite cell stemness factor Pax7 as a target of miR-486. C2C12 myoblasts were cultured with a miR-486 mimetic and RNA-sequencing was performed. Gene enrichment analysis revealed that several genes involved in sarcomerogenesis and extracellular matrix (ECM) were downregulated. Our data suggest that circulating miR-486 transported by EVs is elevated in individuals with CP and that miR-486 alters the transcriptome of myoblasts affecting both ECM- and sarcomerogenesis-related genes, providing a link to the skeletal muscle alterations observed in individuals with CP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vechetti, Norrbom, Alkner, Hjalmarsson, Palmcrantz, Pontén, Pingel, von Walden and Fernandez-Gonzalo.)

Introduction: Depression is common, increasing among adolescents and carries risk of disability, lower educational achievements, cardiovascular disease, substance abuse, self-harm and suicide. The effects of evidence-based treatments with medication or psychotherapy are modest. Aerobic exercise is a promising intervention for adolescents with depression, but available studies are hampered by methodological shortcomings. This study aims to evaluate aerobic group exercise versus an active comparator of leisure group activities in adolescents from clinical services with mild-to-moderate depression., Methods and Analysis: This study is a multicentre randomised controlled trial at four psychiatric clinics in Sweden. Participants (n=122) will be randomised 1:1 to group exercise delivered by exercise professionals and supported by mental health (MH) workers or leisure activities lead by the same MH workers for 1 hour three times a week for 12 weeks. Participants will be assessed at baseline, single blind after 13 weeks and 26 weeks and openly after 1 year. Participants randomised to the leisure group will be offered exercise in the open phase. The primary outcome is clinician-rated Children's Depression Rating Scale-Revised. Secondary outcomes are self-rated Quick Inventory of Depressive Symptomatology, self-rated functioning; clinician-rated improvement and functioning; objectively measured aerobic capacity, muscular strength, muscular endurance, body composition and presence or activity of selected biological markers of neuroprotection and neuroinflammation in blood samples. Further outcomes are cost-effectiveness and adolescents', parents' and coaches' experiences of the interventions and an exploration of how the adolescents' health and lifestyle are influenced by the interventions through qualitative interviews., Ethics and Dissemination: The study is approved by the Swedish Ethical Review Authority (Ref. 2021-05307-01). Informed consent in writing will be provided from patients and parents of participants below 15 years of age. The results of this study will be communicated to the included participants and healthcare providers and also submitted for publication in peer-reviewed journals., Trial Registration Number: NCT05076214., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mitochondrial-derived peptides (MDPs) humanin (HN) and mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) are involved in cell survival, suppression of apoptosis, and metabolism. Circulating levels of MDPs are altered in chronic diseases such as diabetes type 2 and chronic kidney disease. Whether acute resistance (RE) or endurance (EE) exercise modulates circulating levels of HN and MOTS-c in humans is unknown. Following familiarization, subjects were randomized to EE ( n = 10, 45 min cycling at 70% of estimated V̇O 2max ), RE ( n = 10, 4 sets × 7RM, leg press and knee extension), or control (CON, n = 10). Skeletal muscle biopsies and blood samples were collected before and at 30 min and 3 h following exercise. Plasma concentration of HN and MOTS-c, skeletal muscle MOTS-c as well as gene expression of exercise-related genes were analyzed. Acute EE and RE promoted changes in skeletal muscle gene expression typically seen in response to each exercise modality (c-Myc, 45S pre-rRNA, PGC-1α-total, and PGC-1α-ex1b). At rest, circulating levels of HN were positively correlated to MOTS-c levels and age. Plasma levels of MDPs were not correlated to fitness outcomes [V̇O 2max , leg strength, or muscle mitochondrial (mt) DNA copy number]. Circulating levels of HN were significantly elevated by acute EE but not RE. MOTS-C levels showed a trend to increase after EE. These results indicate that plasma MDP levels are not related to fitness status but that acute EE increases circulating levels of MDPs, in particular HN. NEW & NOTEWORTHY In this manuscript, we report for the first time, to our knowledge, the response of circulating levels of mitochondrial-derived peptides humanin and MOTS-c to acute resistance and endurance exercise. Our data support that acute endurance exercise stimulates MDP levels in plasma, whereas acute resistance exercise does not.

Key Points: Ribosome biogenesis and MYC transcription are associated with acute resistance exercise (RE) and are distinct from endurance exercise in human skeletal muscle throughout a 24 h time course of recovery. A PCR-based method for relative ribosomal DNA (rDNA) copy number estimation was validated by whole genome sequencing and revealed that rDNA dosage is positively correlated with ribosome biogenesis in response to RE. Acute RE modifies rDNA methylation patterns in enhancer, intergenic spacer and non-canonical MYC-associated regions, but not the promoter. Myonuclear-specific rDNA methylation patterns with acute mechanical overload in mice corroborate and expand on rDNA findings with RE in humans. A genetic predisposition for hypertrophic responsiveness may exist based on rDNA gene dosage., Abstract: Ribosomes are the macromolecular engines of protein synthesis. Skeletal muscle ribosome biogenesis is stimulated by exercise, although the contribution of ribosomal DNA (rDNA) copy number and methylation to exercise-induced rDNA transcription is unclear. To investigate the genetic and epigenetic regulation of ribosome biogenesis with exercise, a time course of skeletal muscle biopsies was obtained from 30 participants (18 men and 12 women; 31 ± 8 years, 25 ± 4 kg m -2 ) at rest and 30 min, 3 h, 8 h and 24 h after acute endurance (n = 10, 45 min cycling, 70% V ̇ O 2 max ) or resistance exercise (n = 10, 4 × 7 × 2 exercises); 10 control participants underwent biopsies without exercise. rDNA transcription and dosage were assessed using quantitative PCR and whole genome sequencing. rDNA promoter methylation was investigated using massARRAY EpiTYPER and global rDNA CpG methylation was assessed using reduced-representation bisulphite sequencing. Ribosome biogenesis and MYC transcription were associated primarily with resistance but not endurance exercise, indicating preferential up-regulation during hypertrophic processes. With resistance exercise, ribosome biogenesis was associated with rDNA gene dosage, as well as epigenetic changes in enhancer and non-canonical MYC-associated areas in rDNA, but not the promoter. A mouse model of in vivo metabolic RNA labelling and genetic myonuclear fluorescence labelling validated the effects of an acute hypertrophic stimulus on ribosome biogenesis and Myc transcription, and also corroborated rDNA enhancer and Myc-associated methylation alterations specifically in myonuclei. The present study provides the first information on skeletal muscle genetic and rDNA gene-wide epigenetic regulation of ribosome biogenesis in response to exercise, revealing novel roles for rDNA dosage and CpG methylation., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Exercise training prevents multiple diseases, yet the molecular mechanisms that drive exercise adaptation are incompletely understood. To address this, we create a computational framework comprising data from skeletal muscle or blood from 43 studies, including 739 individuals before and after exercise or training. Using linear mixed effects meta-regression, we detect specific time patterns and regulatory modulators of the exercise response. Acute and long-term responses are transcriptionally distinct and we identify SMAD3 as a central regulator of the exercise response. Exercise induces a more pronounced inflammatory response in skeletal muscle of older individuals and our models reveal multiple sex-associated responses. We validate seven of our top genes in a separate human cohort. In this work, we provide a powerful resource ( www.extrameta.org ) that expands the transcriptional landscape of exercise adaptation by extending previously known responses and their regulatory networks, and identifying novel modality-, time-, age-, and sex-associated changes.

Objective: To investigate the potential of an acute bout of transcranial electrical stimulation to induce anabolic signalling., Design: Experimental intervention on healthy subjects., Subjects: Ten healthy subjects, 5 women and 5 men (mean age (standard deviation (SD) 32 years (SD 4))., Methods: The quadriceps muscle was stimulated at a frequency of 10 Hz for 10 s, followed by 20 s of rest, repeated 40 times over 20 min. Electromyography and force data were collected for all transcranial electrical stimulation sequences. Muscle biopsies were obtained from the vastus lateralis muscle before and 1 and 3 h after stimulation., Results: One bout of transcranial electrical stimulation decreased phosphorylation of AKT at Thr308 (1 h: -29%, 3 h: -38%; p < 0.05) and mTOR phosphorylation at Ser2448 (1 h: -10%; ns, 3 h: -21%; p < 0.05), both in the anabolic pathway. Phosphorylation of AMPK, ACC and ULK1 were not affected. c-MYC gene expression was unchanged following transcranial electrical stimulation, but rDNA transcription decreased (1 h: -28%, 3 h: -19%; p < 0.05). PGC1α-ex1b mRNA increased (1 h: 2.3-fold, 3 h: 2.6-fold; p < 0.05), which also correlated with vastus lateralis electromyography activity, while other PGC-1α variants were unchanged., Conclusion: Acute transcranial electrical stimulation of skeletal muscle in weight-bearing healthy individuals did not induce anabolic signalling, and some signs of impaired muscle anabolism were detected, suggesting limited potential in preventing muscle wasting.

Purpose: Whether the benefits of exercise during chemotherapy continue into survivorship is not well-known. Here, the aim was to examine the effects of two exercise interventions on self-reported health-related and objectively measured physiological outcomes 12 months following commencement of chemotherapy., Methods: Two hundred and forty women with breast cancer stage I-IIIa were randomized to 16 weeks of high-intensity aerobic interval training combined with either resistance training (RT-HIIT), or moderate-intensity aerobic training (AT-HIIT), or to usual care (UC)., Primary Outcome: cancer-related fatigue (CRF); secondary outcomes: quality of life (QoL), symptom burden, muscle strength, cardiorespiratory-fitness, body mass, and return to work., Results: Compared to UC, both RT-HIIT and AT-HIIT significantly counteracted increases in total CRF (ES = - 0.34; ES = - 0.10), daily life CRF (ES=-0.76; ES=-0.50, and affective CRF (ES=-0.60; ES=-0.39). Both RT-HIIT and AT-HIIT reported significantly lower total symptoms (ES = - 0.46, ES = - 0.46), and displayed gains in lower limb (ES = 0.73; ES = 1.03) and handgrip muscle strength (surgery side ES = 0.70, ES = 0.71; non-surgery side ES = 0.57, ES = 0.59). AT-HIIT displayed significant reductions in body mass (ES = - 0.24), improved QoL: role (ES = 0.33) and emotional functioning (ES = 0.40), and a larger proportion had returned to work (p = 0.02) vs UC., Conclusion: These findings emphasize the beneficial effects of supervised high-intensity exercise during chemotherapy to improve the health and to reduce societal costs associated with prolonged sick leave for patients with breast cancer several months following chemotherapy., Implications for Cancer Survivors: These findings provide important information with substantial positive consequences for breast cancer survivorship. High-intensity exercise programs during chemotherapy and support to maintain physical activity can be a powerful strategy to manage or prevent many of the short- and long-term adverse effects of treatment for the increasing cohort of cancer survivors.

Exercise has been suggested to ameliorate the detrimental effects of chemotherapy on skeletal muscle. The aim of this study was to compare the effects of different exercise regimens with usual care on skeletal muscle morphology and mitochondrial markers in patients being treated with chemotherapy for breast cancer. Specifically, we compared moderate-intensity aerobic training combined with high-intensity interval training (AT-HIIT) and resistance training combined with high-intensity interval training (RT-HIIT) with usual care (UC). Resting skeletal muscle biopsies were obtained pre- and postintervention from 23 randomly selected women from the OptiTrain breast cancer trial who underwent RT-HIIT, AT-HIIT, or UC for 16 wk. Over the intervention, citrate synthase activity, muscle fiber cross-sectional area, capillaries per fiber, and myosin heavy chain isoform type I were reduced in UC, whereas RT-HIIT and AT-HIIT were able to counteract these declines. AT-HIIT promoted up-regulation of the electron transport chain protein levels vs. UC. RT-HIIT favored satellite cell count vs. UC and AT-HIIT. There was a significant association between change in citrate synthase activity and self-reported fatigue. AT-HIIT and RT-HIIT maintained or improved markers of skeletal muscle function compared with the declines found in the UC group, indicating a sustained trainability in addition to the preservation of skeletal muscle structural and metabolic characteristics during chemotherapy. These findings highlight the importance of supervised exercise programs for patients with breast cancer during chemotherapy.-Mijwel, S., Cardinale, D. A., Norrbom, J., Chapman, M., Ivarsson, N., Wengström, Y., Sundberg, C. J., Rundqvist, H. Exercise training during chemotherapy preserves skeletal muscle fiber area, capillarization, and mitochondrial content in patients with breast cancer.

Background: Advanced therapeutic strategies are often accompanied by significant adverse effects, which warrant equally progressive countermeasures. Physical exercise has proven an effective intervention to improve physical function and reduce fatigue in patients undergoing chemotherapy. Effects of high-intensity interval training (HIIT) in this population are not well established although HIIT has proven effective in other clinical populations. The aim of the OptiTrain trial was to examine the effects of concurrent resistance and high-intensity interval training (RT-HIIT) or concurrent moderate-intensity aerobic and high-intensity interval training (AT-HIIT), to usual care (UC) on pain sensitivity and physiological outcomes in patients with breast cancer during chemotherapy., Methods: Two hundred and forty women were randomized to 16 weeks of RT-HIIT, AT-HIIT, or UC., Outcomes: cardiorespiratory fitness, muscle strength, body mass, hemoglobin levels, and pressure-pain threshold., Results: Pre- to post-intervention, RT-HIIT (ES = 0.41) and AT-HIIT (ES = 0.42) prevented the reduced cardiorespiratory fitness found with UC. Handgrip strength (surgery side: RT-HIIT vs. UC: ES = 0.41, RT-HIIT vs. AT-HIIT: ES = 0.28; non-surgery side: RT-HIIT vs. UC: ES = 0.35, RT-HIIT vs. AT-HIIT: ES = 0.22) and lower-limb muscle strength (RT-HIIT vs. UC: ES = 0.66, RT-HIIT vs. AT-HIIT: ES = 0.23) were significantly improved in the RT-HIIT. Increases in body mass were smaller in RT-HIIT (ES = - 0.16) and AT-HIIT (ES = - 0.16) versus UC. RT-HIIT reported higher pressure-pain thresholds than UC (trapezius: ES = 0.46, gluteus: ES = 0.53) and AT-HIIT (trapezius: ES = 0.30)., Conclusion: Sixteen weeks of RT-HIIT significantly improved muscle strength and reduced pain sensitivity. Both exercise programs were well tolerated and were equally efficient in preventing increases in body mass and in preventing declines in cardiorespiratory fitness. These results highlight the importance of implementing a combination of resistance and high-intensity interval training during chemotherapy for women with breast cancer.

The striated activator of rho-signaling (STARS) protein acts as a link between external stimuli and exercise adaptation such as muscle hypertrophy. However, the acute and long-term adaptational response of STARS is still unclear. This study aimed at investigating the acute and long-term endurance training response on the mRNA and protein expression of STARS and its related upstream and downstream factors in human skeletal muscle. mRNA and protein levels of STARS and related factors were assessed in skeletal muscle of healthy young men and women following an acute bout of endurance exercise (n = 15) or 12 weeks of one-legged training (n = 23). Muscle biopsies were obtained before (acute and long-term), at 30 min, 2, and 6 h following acute exercise, and at 24 h following both acute exercise and long-term training. Following acute exercise, STARS mRNA was significantly elevated 3.9-fold at 30 min returning back to baseline 24 h after exercise. STARS protein levels were numerically but nonsignificantly increased 7.2-fold at 24 h. No changes in STARS or ERRα mRNA or STARS protein expression were seen following long-term training. PGC-1α mRNA increased 1.7-fold following long-term training. MRTF-A mRNA was increased both following acute exercise and long-term training, in contrast to SRF mRNA and protein which did not change. STARS mRNA is acutely upregulated with exercise, but there is no cumulative effect to long-term training as seen in PGC-1α mRNA expression. Exercise intensity might play a role in manifestation of protein expression, suggesting a more complex regulation of STARS., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Increased mitochondrial content is a hallmark of exercise-induced skeletal muscle remodeling. For this process, considerable evidence underscores the involvement of transcriptional coactivators in mediating mitochondrial biogenesis. However, our knowledge regarding the role of transcriptional corepressors is lacking. In this study, we assessed the association of the transcriptional corepressor Rb family proteins, Rb and p107, with endurance exercise-induced mitochondrial adaptation in human skeletal muscle. We showed that p107, but not Rb, protein levels decrease by 3 weeks of high-intensity interval training. This is associated with significant inverse association between p107 and exercise-induced improved mitochondrial oxidative phosphorylation. Indeed, p107 showed significant reciprocal correlations with the protein contents of representative markers of mitochondrial electron transport chain complexes. These findings in human skeletal muscle suggest that attenuated transcriptional repression through p107 may be a novel mechanism by which exercise stimulates mitochondrial biogenesis following exercise., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Humanin (HN) is a mitochondrially encoded and secreted peptide linked to glucose metabolism and tissue protecting mechanisms. Whether skeletal muscle HN gene or protein expression is influenced by exercise remains unknown. In this intervention study we show, for the first time, that HN protein levels increase in human skeletal muscle following 12 weeks of resistance training in persons with prediabetes. Male subjects (n = 55) with impaired glucose regulation (IGR) were recruited and randomly assigned to resistance training, Nordic walking or a control group. The exercise interventions were performed three times per week for 12 weeks with progressively increased intensity during the intervention period. Biopsies from the vastus lateralis muscle and venous blood samples were taken before and after the intervention. Skeletal muscle and serum protein levels of HN were analyzed as well as skeletal muscle gene expression of the mitochondrially encoded gene MT-RNR2, containing the open reading frame for HN To elucidate mitochondrial training adaptation, mtDNA, and nuclear DNA as well as Citrate synthase were measured. Skeletal muscle HN protein levels increased by 35% after 12 weeks of resistance training. No change in humanin protein levels was seen in serum in any of the intervention groups. There was a significant correlation between humanin levels in serum and the improvements in the 2 h glucose loading test in the resistance training group. The increase in HN protein levels in skeletal muscle after regular resistance training in prediabetic males may suggest a role for HN in the regulation of glucose metabolism. Given the preventative effect of exercise on diabetes type 2, the role of HN as a mitochondrially derived peptide and an exercise-responsive mitokine warrants further investigation., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Key Points: Mitochondrial respiratory sensitivity to ADP is thought to influence muscle fitness and is partly regulated by cytosolic-mitochondrial diffusion of ADP or phosphate shuttling via creatine/phosphocreatine (Cr/PCr) through mitochondrial creatine kinase (mtCK). Previous measurements of respiration in vitro with Cr (saturate mtCK) or without (ADP/ATP diffusion) show mixed responses of ADP sensitivity following acute exercise vs. less sensitivity after chronic exercise. In human muscle, modelling in vivo 'exercising' [Cr:PCr] during in vitro assessments revealed novel responses to exercise that differ from detections with or without Cr (±Cr). Acute exercise increased ADP sensitivity when measured without Cr but had no effect ±Cr or with +Cr:PCr, whereas chronic exercise increased sensitivity ±Cr but lowered sensitivity with +Cr:PCr despite increased markers of mitochondrial oxidative capacity. Controlling in vivo conditions during in vitro respiratory assessments reveals responses to exercise that differ from typical ±Cr comparisons and challenges our understanding of how exercise improves metabolic control in human muscle., Abstract: Mitochondrial respiratory control by ADP (Kmapp ) is viewed as a critical regulator of muscle energy homeostasis. However, acute exercise increases, decreases or has no effect on Kmapp in human muscle, whereas chronic exercise surprisingly decreases sensitivity despite greater mitochondrial content. We hypothesized that modelling in vivo mitochondrial creatine kinase (mtCK)-dependent phosphate-shuttling conditions in vitro would reveal increased sensitivity (lower Kmapp ) after acute and chronic exercise. The Kmapp was determined in vitro with 20 mm Cr (+Cr), 0 mm Cr (-Cr) or 'in vivo exercising' 20 mm Cr/2.4 mm PCr (Cr:PCr) on vastus lateralis biopsies sampled from 11 men before, immediately after and 3 h after exercise on the first, fifth and ninth sessions over 3 weeks. Dynamic responses to acute exercise occurred throughout training, whereby the first session did not change Kmapp with in vivo Cr:PCr despite increases in -Cr. The fifth session decreased sensitivity with Cr:PCr or +Cr despite no change in -Cr. Chronic exercise increased sensitivity ±Cr in association with increased electron transport chain content (+33-62% complexes I-V), supporting classic proposals that link increased sensitivity to oxidative capacity. However, in vivo Cr:PCr reveals a perplexing decreased sensitivity, contrasting the increases seen ±Cr. Functional responses occurred without changes in fibre type or proteins regulating mitochondrial-cytosolic energy exchange (mtCK, VDAC and ANT). Despite the dynamic responses seen with ±Cr, modelling in vivo phosphate-shuttling conditions in vitro reveals that ADP sensitivity is unchanged after high-intensity exercise and is decreased after training. These findings challenge our understanding of how exercise regulates skeletal muscle energy homeostasis., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

Individuals with high skeletal muscle mitochondrial content have a lower risk to acquire cardiovascular and metabolic disease, obesity, and type II diabetes. Regular endurance training increases mitochondrial density through a complex network of transcriptional regulators that in an accumulated way are affected by each single exercise bout. The aim of the present study was to investigate the effect of a single exercise bout on the levels of PGC-1α and related regulatory factors important for the initial phase of skeletal muscle adaptation. Ten men and ten women were randomized to either an exercise group (60 min cycling at a work load corresponding to 70% of peak oxygen uptake) or a nonexercising control group. Skeletal muscle biopsies were taken before, at 30 min, and at 2, 6, and 24 h after the intervention. Twenty-two mRNA transcripts and five proteins were measured. With exercise, protein levels of PGC-1α-ex1b increased, and this elevation occurred before that of total PGC-1α protein. We also demonstrated the existence and postexercise expression pattern of two LIPIN-1 (LIPIN-1α and LIPIN-1β) and three NCoR1 (NCoR1-1, NCoR1-2, and NCoR1-3) isoforms in human skeletal muscle. The present study contributes new insights into the initial signaling events following a single bout of exercise and emphasizes PGC-1α-ex1b as the most exercise-responsive PGC-1α isoform., (Copyright © 2015 the American Physiological Society.)

Breast cancer type 1 (BRCA1) susceptibility protein is expressed across multiple tissues including skeletal muscle. The overall objective of this investigation was to define a functional role for BRCA1 in skeletal muscle using a translational approach. For the first time in both mice and humans, we identified the presence of multiple isoforms of BRCA1 in skeletal muscle. In response to an acute bout of exercise, we found increases in the interaction between the native forms of BRCA1 and the phosphorylated form of acetyl-CoA carboxylase. Decreasing BRCA1 content using a shRNA approach in cultured primary human myotubes resulted in decreased oxygen consumption by the mitochondria and increased reactive oxygen species production. The decreased BRCA1 content also resulted in increased storage of intracellular lipid and reduced insulin signaling. These results indicate that BRCA1 plays a critical role in the regulation of metabolic function in skeletal muscle. Collectively, these data reveal BRCA1 as a novel target to consider in our understanding of metabolic function and risk for development of metabolic-based diseases.

Recently, a truncated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) splice variant, PGC-1α4, that originates from the alternative promoter was shown to be induced by resistance exercise and to elicit muscle hypertrophy without coactivation of "classical" PGC-1α targets involved in mitochondrial biogenesis and angiogenesis. In order to test if distinct physiological adaptations are characterized by divergent induction of PGC-1α splice variants, we investigated the expression of truncated and nontruncated PGC-1α splice variants and PGC-1α transcripts originating from the alternative and the proximal promoter, in human skeletal muscle in response to endurance and resistance exercise. Both total PGC-1α and truncated PGC-1α mRNA expression were increased 2 h after endurance (P < 0.01) and resistance exercise (P < 0.01), with greater increases after endurance exercise (P < 0.05). Expression of nontruncated PGC-1α increased significantly in both exercise groups (P < 0.01 for both groups) without any significant differences between the groups. Both endurance and resistance exercise induced truncated as well as nontruncated PGC-1α transcripts from both the alternative and the proximal promoter. Further challenging the hypothesis that induction of distinct PGC-1α splice variants controls exercise adaptation, both nontruncated and truncated PGC-1α transcripts were induced in AICAR-treated human myotubes (P < 0.05). Thus, contrary to our hypothesis, resistance exercise did not specifically induce the truncated forms of PGC-1α. Induction of truncated PGC-1α splice variants does not appear to underlie distinct adaptations to resistance versus endurance exercise. Further studies on the existence of numerous splice variants originating from different promoters are needed.

In the present study, the effect of exercise training on the expression and activity of matrix metalloproteinases (MMPs) in the human skeletal muscle was investigated. Ten subjects exercised one leg for 45 min with restricted blood flow and then exercised the other leg at the same absolute workload with unrestricted blood flow. The exercises were conducted four times per week for 5 wk. Biopsies were taken from the vastus lateralis muscles of both legs at rest before the training period, after 10 days and 5 wk of training, and 2 h after the first exercise bout for analysis of MMP and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA, enzyme activity, and protein expression. Levels of MMP-2, MMP-14, and TIMP-1 mRNA in muscle tissue increased after 10 days of training regardless of blood flow condition. MMP-2 mRNA level in laser-dissected myofibers and MMP-2 activity in whole muscle increased with training. The level of MMP-9 mRNA and activity increased after the first bout of exercise. Although MMP-9 mRNA levels appeared to be very low, the activity of MMP-9 after a single bout of exercise was similar to that of MMP-2 after 10 days of exercise. MMP-2 and MMP-9 protein was both present throughout the extracellular matrix of the muscle, both around fibers and capillaries, but MMP-2 was also present within the skeletal muscle fibers. These results show that MMPs are activated in skeletal muscle in nonpathological conditions such as voluntary exercise. The expression and time pattern indicate differences between the MMPs in regards of production sites as well as in the regulating mechanism.

Aims: Studies from genetically modified animals have been instrumental in highlighting genes and their products involved in the regulation of muscle fibre type and oxidative phenotypes; however, evidence in humans is limited. Our aim was therefore to investigate expression of those genes implicated in the regulation of oxidative fibre phenotypes in humans., Methods: Using quantitative polymerase chain reaction we determined mRNA expression of selected genes in skeletal muscle from three different groups, displaying physiological and pathological variations in muscle fibre type, activity and skeletal muscle metabolism respectively: (i) elite athletes (cyclists), with an increased proportion of type I slow twitch, oxidative fibres, (ii) normally active subjects with an average fibre type distribution, and (iii) spinal cord-injured subjects with a low proportion of type I fibres., Results: Skeletal muscle mRNA expression of calcineurin Aalpha and Abeta, peroxisome proliferator-activated receptor (PPAR)-alpha and -delta, and PPAR gamma coactivator (PGC)-1alpha and -1beta was determined. Calcineurin Aalpha and calcineurin Abeta mRNA expression was similar between groups. In contrast, mRNA expression of PPARalpha, PPARdelta, PGC-1alpha and -1beta was increased in athletes, when compared with normally active subjects. Furthermore, mRNA expression of PPARalpha, PPARdelta, PGC-1alpha and -1beta was reduced in spinal cord-injured subjects. Additionally, PPARalpha, PPARdelta and PGC-1alpha correlated with oxidative fibre content., Conclusion: Skeletal muscle mRNA expression of PPARalpha, PPARdelta, PGC-1alpha and -1beta reflects differences in type I muscle fibres associated with pathologically and physiologically induced skeletal muscle fibre type differences.

The mechanisms that regulate intramyocellular triglycerol (IMTG) storage and mobilization are largely unknown. However, during the last decades several intracellular fatty acid binding proteins (FABPs) have been identified. FABP3 is the dominating FABP in skeletal muscle. Expression of additional FABPs is suggested from findings in FABP3-null mutated mice. In the present study, our aims were to investigate if FABP4 is expressed within skeletal muscle fibers and if FABP3 and FABP4 are more abundant in skeletal muscle fibers in endurance-trained than in control subjects. We show that FABP4 protein is expressed within the skeletal muscle fibers and that FABP4 mRNA and protein are more abundant in the endurance trained subjects. Still, FABP4 is markedly less expressed than FABP3, which is the generally accepted dominating FABP in skeletal muscle tissue.

Physical activity enhances muscle mitochondrial gene expression, while inactivity and mitochondrial dysfunction are both risk factors for developing diabetes. Defective activation of the transcriptional coactivator PGC-1alpha may contribute to the gene expression pattern observed in diabetic and insulin-resistant skeletal muscle. We proposed that greater insight into the mitochondrial component of skeletal muscle "diabetes" would be possible if the clinical transcriptome data were contrasted with local muscle inactivity-induced modulation of mitochondrial genes in otherwise healthy subjects. We studied PPARGC1A (PGC-1alpha), PPARGC1B (PGC-1beta), NRF1, and a variety of mitochondrial DNA (mtDNA) and nuclear-encoded mitochondrial genes critical for oxidative phosphorylation in soleus muscle biopsies obtained from six healthy men and women before and after 5 weeks of local muscle inactivity. Muscle inactivity resulted in a coordinated down-regulation of PGC-1alpha and genes involved with mitochondrial metabolism, including muscle substrate delivery genes. Decreased expression of the mtDNA helicase Twinkle was related to the decline in mitochondrial RNA polymerase (r = 0.83, p < 0.04), suggesting that mtDNA transcription and replication are coregulated in human muscle tissue. In contrast to the situation in diabetes, PGC-1beta expression was not significantly altered, while NRF1 expression was actually up-regulated following muscle inactivity. We can conclude that reduced PGC-1alpha expression described in Type 2 diabetes may be partly explained by muscle inactivity. Further, although diabetes patients are typically inactive, our analysis indicates that local muscle inactivity may not be expected to contribute to the decreased NRF1 and PGC-1beta expression noted in insulin-resistant and Type 2 diabetes patients, suggesting these changes may be more disease specific.

Angiogenic gene therapy in angina pectoris has been disappointing so far. Reasons might be that the administered genes already are overexpressed in ischemic myocardium, or that atrial and brain natriuretic peptides (ANP and BNP) are overexpressed, as they have anti-angiogenic effects. Five stable angina pectoris patients without heart failure were studied. Left ventricular biopsies were taken during coronary by-pass surgery from a region with stress-inducible ischemia and from a normal region. Both ANP and BNP but not vascular endothelial growth factor (VEGF) and VEGF-receptor 1 and 2 were overexpressed in ischemic regions compared to non-ischemic regions as measured by real-time PCR. The expression of 15 other angiogenic genes measured by oligonucleotide arrays was not consistently increased in ischemic regions. The overexpression of ANP and BNP suggests an anti-angiogenic effect in ischemic heart disease. The lack of overexpression of angiogenic genes supports the concept of therapeutic overexpression of these genes.

Endurance training leads to many adaptational changes in several tissues. In skeletal muscle, fatty acid usage is enhanced and mitochondrial content is increased. The exact molecular mechanisms regulating these functional and structural changes remain to be elucidated. Contractile activity-induced metabolic perturbation has repeatedly been shown to be important for the induction of mitochondrial biogenesis. Recent reports suggest that the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha)/mitochondrial transcription factor A (Tfam) pathway is involved in exercise-induced mitochondrial biogenesis. In the present study, nine healthy men performed two 45-min bouts of one-legged knee extension exercise: one bout with restricted blood flow, and the other with nonrestricted blood flow to the working muscle. Muscle biopsies were obtained from the vastus lateralis muscle before exercise and at 0, 30, 120, and 360 min after the exercise bout. Biopsies were analyzed for whole muscle, as well as fiber-type specific mRNA expression of myocyte-enriched calcineurin interacting protein (MCIP)-1, PGC-1alpha, and downstream mitochondrial transcription factors. A novel finding was that, in human skeletal muscle, PGC-1alpha mRNA increased more after exercise with restricted blood flow than in the nonrestricted condition. No changes were observed for the mRNA of NRF-1, Tfam, mitochondrial transcription factor B1, and mitochondrial transcription factor B2. Muscle fiber type I and type II did not differ in the basal PGC-1alpha mRNA levels or in the expression increase after ischemic training. Another novel finding was that there was no difference between the restricted and nonrestricted exercise conditions in the increase of MCIP-1 mRNA, a marker for calcineurin activation. This suggests that calcineurin may be activated by exercise in humans and does not exclude that calcineurin could play a role in PGC-1 transcription activation in human skeletal muscle.