Bone remodeling in survivors of pediatric hematopoietic stem cell transplantation: Impact of heavy resistance training.

BACKGROUND: Early-onset osteoporosis is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT). It remains unknown if physical training can improve bone formation in these patients, as the transplantation procedure may cause sustained dysregulation of the bone-forming osteoblast progenitor cells. OBJECTIVE: We aimed to explore the effect of resistance training on bone remodeling in long-term survivors of pediatric HSCT. PROCEDURE: In this prospective, controlled intervention study, we included seven HSCT survivors and 15 age- and sex-matched healthy controls. The participants completed a 12-week heavy load, lower extremity resistance training intervention with three weekly sessions. We measured fasting serum levels of the bone formation marker "N-terminal propeptide of type I procollagen" (P1NP), and the bone resorption marker "C-terminal telopeptide of type I collagen" (CTX). The hypothesis was planned before data collection began. The trial was registered at Clinicaltrials.gov before including the first participant, with trial registration no. NCT04922970. RESULTS: Resistance training led to significantly increased levels of fasting P1NP in both patients (from 57.62 to 114.99 ng/mL, p = .03) and controls (from 66.02 to 104.62 ng/mL, p < .001). No significant changes in fasting CTX levels were observed. CONCLUSIONS: Despite previous high-dose cytotoxic therapy, long-term survivors of pediatric HSCT respond to resistance training with improvement of bone formation, comparable to that of healthy controls. This suggests that resistance training might be a promising non-pharmacological approach to prevent the early decline in bone mass, and should be considered as part of a follow-up program to counteract long-term sequela after pediatric HSCT.

The COVID-19 in athletes (COVA) study: a national study on cardio-pulmonary involvement of SARS-CoV-2 infection among elite athletes.

Background: COVID-19 can cause cardiopulmonary involvement. Physical activity and cardiac complications can worsen prognosis, while pulmonary complications can reduce performance. Aims: To determine the prevalence and clinical implications of SARS-CoV-2 cardiopulmonary involvement in elite athletes. Methods: An observational study between 1 July 2020 and 30 June 2021 with the assessment of coronary biomarkers, electrocardiogram, echocardiography, Holter-monitoring, spirometry, and chest X-ray in Danish elite athletes showed that PCR-tested positive for SARS-CoV-2. The cohort consisted of male football players screened weekly (cohort I) and elite athletes on an international level only tested if they had symptoms, were near-contact, or participated in international competitions (cohort II). All athletes were categorized into two groups based on symptoms and duration of COVID-19: Group 1 had no cardiopulmonary symptoms and duration ≤7 days, and; Group 2 had cardiopulmonary symptoms or disease duration >7 days. Results: In total 121 athletes who tested positive for SARS-CoV-2 were investigated. Cardiac involvement was identified in 2/121 (2%) and pulmonary involvement in 15/121 (12%) participants. In group 1, 87 (72%), no athletes presented with signs of cardiac involvement, and 8 (7%) were diagnosed with radiological COVID-19-related findings or obstructive lung function. In group 2, 34 (28%), two had myocarditis (6%), and 8 (24%) were diagnosed with radiological COVID-19-related findings or obstructive lung function. Conclusions: These clinically-driven data show no signs of cardiac involvement among athletes who tested positive for SARS-CoV-2 infection without cardiopulmonary symptoms and duration <7 days. Athletes with cardiopulmonary symptoms or prolonged duration of COVID-19 display, exercise-limiting cardiopulmonary involvement.

ZAKß is activated by cellular compression and mediates contraction-induced MAP kinase signaling in skeletal muscle.

Mechanical inputs give rise to p38 and JNK activation, which mediate adaptive physiological responses in various tissues. In skeletal muscle, contraction-induced p38 and JNK signaling ensure adaptation to exercise, muscle repair, and hypertrophy. However, the mechanisms by which muscle fibers sense mechanical load to activate this signaling have remained elusive. Here, we show that the upstream MAP3K ZAKß is activated by cellular compression induced by osmotic shock and cyclic compression in vitro, and muscle contraction in vivo. This function relies on ZAKß's ability to recognize stress fibers in cells and Z-discs in muscle fibers when mechanically perturbed. Consequently, ZAK-deficient mice present with skeletal muscle defects characterized by fibers with centralized nuclei and progressive adaptation towards a slower myosin profile. Our results highlight how cells in general respond to mechanical compressive load and how mechanical forces generated during muscle contraction are translated into MAP kinase signaling.

Extreme duration exercise affects old and younger men differently.

AIM & METHODS: Extreme endurance exercise provides a valuable research model for understanding the adaptive metabolic response of older and younger individuals to intense physical activity. Here, we compare a wide range of metabolic and physiologic parameters in two cohorts of seven trained men, age 30 ± 5 years or age 65 ± 6 years, before and after the participants travelled ≈3000 km by bicycle over 15 days. RESULTS: Over the 15-day exercise intervention, participants lost 2-3 kg fat mass with no significant change in body weight. V̇O2 max did not change in younger cyclists, but decreased (p = 0.06) in the older cohort. The resting plasma FFA concentration decreased markedly in both groups, and plasma glucose increased in the younger group. In the older cohort, plasma LDL-cholesterol and plasma triglyceride decreased. In skeletal muscle, fat transporters CD36 and FABPm remained unchanged. The glucose handling proteins GLUT4 and SNAP23 increased in both groups. Mitochondrial ROS production decreased in both groups, and ADP sensitivity increased in skeletal muscle in the older but not in the younger cohort. CONCLUSION: In summary, these data suggest that older but not younger individuals experience a negative adaptive response affecting cardiovascular function in response to extreme endurance exercise, while a positive response to the same exercise intervention is observed in peripheral tissues in younger and older men. The results also suggest that the adaptive thresholds differ in younger and old men, and this difference primarily affects central cardiovascular functions in older men after extreme endurance exercise.

Age-related myofiber atrophy in old mice is reversed by ten weeks voluntary high-resistance wheel running.

OBJECTIVE: Age-related loss of muscle mass and function can be attenuated in rodents with life-long voluntary wheel running with moderate resistance. The present study assessed if sarcopenia could be counteracted with ten weeks high intensity training. METHOD: Old (22-23 months) and middle-aged (11 months) mice were divided into three physical activity groups: Ten weeks of voluntary running in wheels with high (HR) or low resistance (LR), or no running wheel (SED). The wheel resistance was 0.5-1.5 g in the LR group and progressed from 5 g to 10 g in the HR group. Six, 8 and 5 old and 8, 9 and 9 middle-aged mice of the SED, LR and HR groups, respectively, were included in the analysis. Wheel activity was monitored throughout the intervention. Muscle mass of the tibialis anterior, gastrocnemius, soleus and plantaris muscles were measured post-mortem. Fiber type distribution and myofiber cross sectional areal (CSA) were quantified in the gastrocnemius and soleus muscles as well as total number of fibers in the soleus muscle. RESULTS: In the SED, the mass of all individual muscles was reduced in the old vs middle-aged (P < 0.001). In the training groups, the old mice ran significantly less, slower and for shorter bouts than the middle-aged throughout the intervention (P < 0.05). HR running increased the gastrocnemius and soleus muscle mass by 6% and 18% respectively in the old compared to SED. Fiber CSA was significantly reduced in the old SED mice, whereas fiber CSA in the old HR gastrocnemius and soleus muscles was comparable to the SED middle-aged. Fiber type shifted from 2b towards 2a in the gastrocnemius muscle of the trained old mice. HR running was more efficient than LR in maintaining muscle mass and myofiber size, and in shifting fiber types. In the middle-aged mice, similar effects were found, but less pronounced. Interestingly, fiber CSA was unaffected by running in the middle-aged. CONCLUSION: Ten weeks of HR running had a positive effect on muscle mass and morphology in both middle-aged and old mice. The old HR fiber CSA was greater than in old SED and comparable to the middle-aged, and the fibers shifted to a more oxidative composition (2b â†’ 2a). Albeit less pronounced, similar training effects were observed in the middle-aged mice despite running faster and longer than the old.

Impact of low-volume concurrent strength training distribution on muscular adaptation.

OBJECTIVES: Military-, rescue- and law-enforcement personnel require a high physical capacity including muscular strength. The present study hypothesized that 9 weeks of volume matched concurrent short frequent training sessions increases strength more efficiently than less frequent longer training sessions. DESIGN: A randomized training intervention study with functional and physiological tests before and after the intervention. METHODS: Military conscripts (n=290) were assigned to micro-training (four 15-min strength and four 15-min endurance bouts weekly); classical-training (one 60-min strength and one 60-min endurance training session weekly) or a control-group (two 60-min standard military physical training sessions weekly). RESULTS: There were no group difference between micro-training and classical-training in measures of strength. Standing long jump remained similar while shotput performance was reduced (P≤0.001) in all three groups. Pull-up performance increased (P≤0.001) in micro-training (7.4±4.6 vs. 8.5±4.0 repetitions, n=59) and classical-training (5.7±4.1 vs. 7.1±4.2 repetitions, n=50). Knee extensor MVC increased (P≤0.01) in all groups (micro-training, n=30, 11.5±8.9%; classical-training, n=24, 8.3±11.5% and control, n=19, 7.5±11.8%) while elbow flexor and hand grip MVC remained similar. Micro-training increased (P≤0.05) type IIa percentage from 32.5±11.0% to 37.6±12.3% (n=20) and control-group increased (P≤0.01) type IIax from 4.4±3.0% to 11.6±7.9% (n=8). In control-group type I, fiber size increased (P≤0.05) from 5121±959µm to 6481±2084µm (n=5). Satellite cell content remained similar in all groups. CONCLUSIONS: Weekly distribution of low-volume concurrent training completed as either eight 15-min bouts or two 60-min sessions of which 50% was strength training did not impact strength gains in a real-world setting.

Preserved capacity for satellite cell proliferation, regeneration, and hypertrophy in the skeletal muscle of healthy elderly men.

Blunted muscle hypertrophy and impaired regeneration with aging have been partly attributed to satellite cell (SC) dysfunction. However, true muscle regeneration has not yet been studied in elderly individuals. To investigate this, muscle injury was induced by 200 electrically stimulated (ES) eccentric contractions of the vastus lateralis (VL) of one leg in seven young (20-31 years) and 19 elderly men (60-73 years). This was followed by 13 weeks of resistance training (RT) for both legs to investigate the capacity for hypertrophy. Muscle biopsies were collected Pre- and Post-RT, and 9 days after ES, for immunohistochemistry and RT-PCR. Hypertrophy was assessed by MRI, DEXA, and immunohistochemistry. Overall, surprisingly comparable responses were observed between the young and elderly. Nine days after ES, Pax7+ SC number had doubled (P < .05), alongside necrosis and substantial changes in expression of genes related to matrix, myogenesis, and innervation (P < .05). Post-RT, VL cross-sectional area had increased in both legs (~15%, P < .05) and SCs/type II fiber had increased ~2-4 times more with ES+RT vs RT alone (P < .001). Together these novel findings demonstrate "youthful" regeneration and hypertrophy responses in human elderly muscle. Furthermore, boosting SC availability in healthy elderly men does not enhance the subsequent muscle hypertrophy response to RT.

Cardiovascular and metabolic health effects of team handball training in overweight women: Impact of prior experience.

PURPOSE: We tested the hypothesis that participation in small-sided team handball training could provide beneficial effects on cardiovascular and metabolic parameters in overweight premenopausal women with special focus on the importance of prior team handball experience. METHODS: A 16-week RCT training intervention was conducted in overweight premenopausal women randomized into three groups: a team handball training group without prior experience (UN; n = 13), a team handball group with prior experience (EXP; n = 10), and an inactive control group (CON; n = 9). Both UN and EXP completed 1.6 ± 0.3 training sessions per week with average heart rates of 84 ± 5 and 85 ± 9% of maximal heart rate, respectively. Cardiovascular and metabolic parameters were assessed before and after the intervention. RESULTS: Compared to CON, UN had significant increases in VO2max  (7 ± 4%) and intermittent endurance performance (26 ± 14%) as well as reduced total fat mass (4 ± 6%), total fat percentage (4 ± 5%), and android fat mass (7 ± 12%), respectively (all P < .05). Compared to UN and CON, EXP displayed increased left ventricular mass and left ventricular mass index (both P < .05) after the training period. There were no significant changes between any of the groups in muscle mass, blood lipids, resting heart rate, and blood pressure (all P > .05). CONCLUSION: Small-sided team handball training in overweight premenopausal women resulted in improvement of VO2max and body composition for participants with minimal team handball experience, indicating that prior team handball experience is not a prerequisite for improving physiological parameters of importance for health. Furthermore, EXP displayed cardiac adaptations, including increased left ventricular mass and left ventricular mass index.

Bone mineral density in lifelong trained male football players compared with young and elderly untrained men.

PURPOSE: The purpose of the present controlled cross-sectional study was to investigate proximal femur and whole-body bone mineral density (BMD), as well as bone turnover profile, in lifelong trained elderly male football players and young elite football players compared with untrained age-matched men. METHODS: One hundred and forty healthy, non-smoking men participated in the study, including lifelong trained football players (FTE, n = 35) aged 65-80 years, elite football players (FTY, n = 35) aged 18-30 years, as well as untrained age-matched elderly (UE, n = 35) and young (UY, n = 35) men. All participants underwent a regional dual-energy X-ray Absorptiometry (DXA) scan of the proximal femur and a whole-body DXA scan to determine BMD. From a resting blood sample, the bone turnover markers (BTMs) osteocalcin, carboxy-terminal type-1 collagen crosslinks (CTX-1), procollagen type-1 amino-terminal propeptide (P1NP), and sclerostin were measured. RESULTS: FTE had 7.3%-12.9% higher (p < 0.05) BMD of the femoral neck, wards, shaft, and total proximal femur in both legs compared to UE, and 9.3%-9.7% higher (p < 0.05) BMD in femoral trochanter in both legs compared to UY. FTY had 24.3%-37.4% higher (p < 0.001) BMD in all femoral regions and total proximal femur in both legs compared to UY. The whole-body DXA scan confirmed these results, with FTE showing similar whole-body BMD and 7.9% higher (p < 0.05) leg BMD compared to UY, and with FTY having 9.6% higher (p < 0.001) whole-body BMD and 18.2% higher (p < 0.001) leg BMD compared to UY. The plasma concentration of osteocalcin, CTX-1, and P1NP were 29%, 53%, and 52% higher (p < 0.01), respectively, in FTY compared to UY. CONCLUSION: BMD of the proximal femur and whole-body BMD are markedly higher in lifelong trained male football players aged 65-80 years and young elite football players aged 18-30 years compared to age-matched untrained men. Elderly football players even show higher BMD in femoral trochanter and leg BMD than untrained young despite an age difference of 47 years.

Improved skeletal muscle mass and strength after heavy strength training in very old individuals.

Age-related loss of muscle mass and function represents personal and socioeconomic challenges. The purpose of this study was to determine the adaptation of skeletal musculature in very old individuals (83+ years) performing 12weeks of heavy resistance training (3×/week) (HRT) compared to a non-training control group (CON). Both groups received similar protein supplementations. We studied 26 participants (86.9±3.2 (SD) (83-94, range) years old) per-protocol. Quadriceps cross-sectional area (CSA) differed between groups at post-test (P<0.05) and increased 1.5±0.7cm2 (3.4%) (P<0.05) in HRT only. The increase in CSA is correlated inversely with the baseline level of CSA (R2=0.43, P<0.02). Thigh muscle isometric strength, isokinetic peak torque and power increased significantly only in HRT by 10-15%, whereas knee extension one-repetition maximum (1 RM) improved by 91%. Physical functional tests, muscle fiber type distribution and size did not differ significantly between groups. We conclude that in protein supplemented very old individuals, heavy resistance training can increase muscle mass and strength, and that the relative improvement in mass is more pronounced when initial muscle mass is low.

Training Does Not Alter Muscle Ceramide and Diacylglycerol in Offsprings of Type 2 Diabetic Patients Despite Improved Insulin Sensitivity.

Ceramide and diacylglycerol (DAG) may be involved in the early phase of insulin resistance but data are inconsistent in man. We evaluated if an increase in insulin sensitivity after endurance training was accompanied by changes in these lipids in skeletal muscle. Nineteen first-degree type 2 diabetes Offsprings (Offsprings) (age: 33.1 ± 1.4 yrs; BMI: 26.4 ± 0.4 kg/m2) and sixteen matched Controls (age: 31.3 ± 1.5 yrs; BMI: 25.3 ± 0.7 kg/m2) performed 10 weeks of endurance training three times a week at 70% of VO2max on a bicycle ergometer. Before and after the intervention a hyperinsulinemic-euglycemic clamp and VO2max test were performed and muscle biopsies obtained. Insulin sensitivity was significantly lower in Offsprings compared to control subjects (p < 0.01) but improved in both groups after 10 weeks of endurance training (Off: 17 ± 6%; Con: 12 ± 9%, p < 0.01). The content of muscle ceramide, DAG, and their subspecies were similar between groups and did not change in response to the endurance training except for an overall reduction in C22:0-Cer (p < 0.05). Finally, the intervention induced an increase in AKT protein expression (Off: 27 ± 11%; Con: 20 ± 24%, p < 0.05). This study showed no relation between insulin sensitivity and ceramide or DAG content suggesting that ceramide and DAG are not major players in the early phase of insulin resistance in human muscle.

Fiber type-specific response of skeletal muscle satellite cells to high-intensity resistance training in dialysis patients.

INTRODUCTION: The aim of this study was to assess the effect of high-intensity resistance training on satellite cell (SC) and myonuclear number in the muscle of patients undergoing dialysis. METHODS: Patients (n = 21) underwent a 16-week control period, followed by 16 weeks of resistance training 3 times weekly. SC and myonuclear number were determined by immunohistochemistry of vastus lateralis muscle biopsy cross-sections. Knee extension torque was tested in a dynamometer. RESULTS: During training, SCs/type I fibers increased by 15%, whereas SCs/type II fibers remained unchanged. Myonuclear content of type II, but not type I, fibers increased with training. Before the control period, the SC content of type II fibers was lower than that of type I fibers, whereas contents were comparable when normalized to fiber area. Torque increased after training. CONCLUSIONS: Increased myonuclear content of type II muscle fibers of dialysis patients who perform resistance training suggests that SC dysfunction is not the limiting factor for muscle growth.

Functional adaptation of tendon and skeletal muscle to resistance training in three patients with genetically verified classic Ehlers Danlos Syndrome.

BACKGROUND: tendon and skeletal muscle function adapts to physical training of resistive nature, but it is unknown to what extent persons with genetically altered connective tissue - who have a higher than normal tendon extensibility - will obtain any effect upon their tendon and muscle when undergoing muscle strength training. We investigated patients with classical Ehlers Danlos Syndrome (EDS) (collagen type V defect) who display articular hypermobility, skin extensibility and tissue fragility. METHODS: subjects underwent strength training 3 times a week for 4 months and were tested before and after intervention in regards to muscle strength, tendon mechanical properties, and muscle function. RESULTS: three subjects completed the scheduled 48 sessions and had no major adverse events. Mean isometric leg extension force and leg extensor power both increased by 8 and 11% respectively (358 to 397 N, and 117 to 123 W). The tendon stiffness was tested and an average increase in response to physical training, from 1795 to 2519 N/mm was found. On average, the training loads both in upper and lower body exercises increased by around 30% over the training period. When testing balance, the average sway-area of the participants decreased by 26% (0.144 to 0.108 m(2)). On the subscale of CIS20 the participants lowered their average subjective fatigue score from 33 to 25. CONCLUSION: in this small pilot study, heavy resistance training was both feasible and effective in classic Ehlers Danlos patients, and the results indicated that both tendon and skeletal muscle properties can be improved also in this patient group when they are subjected to resistance training.

Changed mitochondrial function by pre- and/or postpartum diet alterations in sheep.

In a sheep model, we investigated diet effects on skeletal muscle mitochondria to look for fetal programming. During pregnancy, ewes were fed normally (N) or were 50% food restricted (L) during the last trimester, and lambs born to these ewes received a normal (N) or a high-fat diet (H) for the first 6 mo of life. We examined mitochondrial function in permeabilized muscle fibers from the lambs at 6 mo of age (adolescence) and after 24 mo of age (adulthood). The postpartum H diet for the lambs induced an approximately 30% increase (P < 0.05) of mitochondrial VO(2max) and an approximately 50% increase (P < 0.05) of the respiratory coupling ratio (RCR) combined with lower levels of UCP3 and PGC-1alpha mRNA levels (P < 0.05). These effects proved to be reversible by a normal diet from 6 to 24 mo of age. However, at 24 mo, a long-term effect of the maternal gestational diet restriction (fetal programming) became evident as a lower VO(2max) (approximately 40%, P < 0.05), a lower state 4 respiration (approximately 40%, P < 0.05), and lower RCR ( approximately 15%, P < 0.05). Both PGC-1alpha and UCP3 mRNA levels were increased (P < 0.05). Two analyzed muscles were affected differently, and muscle rich in type I fibers was more susceptible to fetal programming. We conclude that fetal programming, seen as a reduced VO(2max) in adulthood, results from gestational undernutrition. Postnatal high-fat diet results in a pronounced RCR and VO(2max) increase in adolescence. However, these effects are reversible by diet correction and are not maintained in adulthood.

Skeletal muscle adaptation: training twice every second day vs. training once daily.

Low muscle glycogen content has been demonstrated to enhance transcription of a number of genes involved in training adaptation. These results made us speculate that training at a low muscle glycogen content would enhance training adaptation. We therefore performed a study in which seven healthy untrained men performed knee extensor exercise with one leg trained in a low-glycogen (Low) protocol and the other leg trained at a high-glycogen (High) protocol. Both legs were trained equally regarding workload and training amount. On day 1, both legs (Low and High) were trained for 1 h followed by 2 h of rest at a fasting state, after which one leg (Low) was trained for an additional 1 h. On day 2, only one leg (High) trained for 1 h. Days 1 and 2 were repeated for 10 wk. As an effect of training, the increase in maximal workload was identical for the two legs. However, time until exhaustion at 90% was markedly more increased in the Low leg compared with the High leg. Resting muscle glycogen and the activity of the mitochondrial enzyme 3-hydroxyacyl-CoA dehydrogenase increased with training, but only significantly so in Low, whereas citrate synthase activity increased in both Low and High. There was a more pronounced increase in citrate synthase activity when Low was compared with High. In conclusion, the present study suggests that training twice every second day may be superior to daily training.

GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men.

GH administration, either alone or combined with resistance exercise training (RT), has attracted interest as a means of increasing muscle mass and strength in the elderly. In the present study, 31 healthy, elderly men [age, 74 +/- 1 yr (mean +/- SEM)] were assigned to either RT [3 sessions/wk, 3-5 sets of 8-12 repetition maximum (RM)/session] + placebo (n = 8), RT + GH (n = 8), GH (n = 8), or placebo (n = 7) in a randomized, placebo-controlled, double-blinded (RT + placebo and RT + GH) or single-blinded (GH or placebo) design. Measurements of: 1) isokinetic quadriceps muscle strength; 2) quadriceps muscle power; 3) quadriceps muscle fiber type, size, and myosin heavy chain (MHC) composition; 4) quadriceps cross-sectional area (CSA) [nuclear magnetic resonance imaging (NMRI)]; 5) body composition (dual-energy x-ray absorptiometry scanning); and 6) GH-related serum markers were performed at baseline and after 12 wk. The final GH dose was 1.77 +/- 0.18 IU x d(-1) (approximately 7.2 +/- 0.8 microg x kg(-1) x d(-1)). GH alone had no effect on isokinetic quadriceps muscle strength, power, CSA, or fiber size. However, a substantial increase in MHC 2X isoform was observed with GH administration alone, and this may be regarded as a change into a more youthful MHC composition, possibly induced by the rejuvenating of systemic IGF-I levels. RT + placebo caused substantial increases in quadriceps isokinetic strength, power, and CSA; but these RT induced improvements were not further augmented by additional GH administration. In the RT + GH group, there was a significant decrease in MHC 1 and 2X isoforms, whereas MHC 2A increased. RT, therefore, seems to overrule the changes in MHC composition induced by GH administration alone. Changes in body composition confirmed previous reports of decreased fat mass, increased fat-free mass, and unchanged bone mineral content with GH administration. A high incidence of side effects was reported. Our results do not support a role for GH as a means of increasing muscle strength or mass, either alone or combined with RT, in healthy elderly men; although GH administration alone may induce changes in MHC composition.