Cardiovascular, muscular, and skeletal adaptations to recreational team handball training: a randomized controlled trial with young adult untrained men.

PURPOSE: The prevalence of lifestyle diseases has escalated, and effective exercise training programmes are warranted. This study tested the hypothesis that regular participation in small-sided team handball training could provide beneficial health effects on cardiovascular, skeletal, and muscular parameters in young adult untrained men. METHOD: Twenty-six untrained 20-30-year-old men were randomly allocated to either a team handball training group (HG; n = 14), which completed 1.9 ± 0.3 training sessions per week over 12 weeks, or an inactive control group (CG; n = 12). Physiological training adaptations were assessed pre- and post interventions by DXA scans, blood samples, muscle biopsies, and physical tests. RESULTS: The average heart rate during training was equivalent to 84 ± 4% of maximal heart rate. Compared to CG, HG displayed significant increases in VO2max (11 ± 6%), proximal femur bone mineral density (2 ± 1%), whole-body bone mineral content (2 ± 1%), intermittent endurance performance (32 ± 16%), incremental treadmill test performance (16 ± 7%) and muscle citrate synthase activity (22 ± 28%) as well as decreases in total fat mass (7 ± 7%) and total fat percentage (6 ± 7%) (all p < 0.05). There were no significant changes in muscle mass, blood pressure, resting heart rate, muscle hydroxyl-acyl-dehydrogenase activity, or blood lipids (all p > 0.05). CONCLUSION: Participation in regular recreational team handball training was associated with positive cardiovascular, skeletal, and muscular adaptations, including increased maximal oxygen uptake, increased muscle enzymatic activity, and improved bone mineralization as well as lower fat percentage. These findings suggest that recreational team handball training may be an effective health-promoting activity for young adult men.

Correction to: Cardiovascular, muscular, and skeletal adaptations to recreational team handball training: a randomized controlled trial with young adult untrained men.

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Effects of 6-month aerobic interval training on skeletal muscle metabolism in middle-aged metabolic syndrome patients.

Aerobic interval training (AIT) improves the health of metabolic syndrome patients (MetS) more than moderate intensity continuous training. However, AIT has not been shown to reverse all metabolic syndrome risk factors, possibly due to the limited duration of the training programs. Thus, we assessed the effects of 6 months of AIT on cardio-metabolic health and muscle metabolism in middle-aged MetS. Eleven MetS (54.5±0.7 years old) underwent 6 months of 3 days a week supervised AIT program on a cycle ergometer. Cardio-metabolic health was assessed, and muscle biopsies were collected from the vastus lateralis prior and at the end of the program. Body fat mass (-3.8%), waist circumference (-1.8%), systolic (-10.1%), and diastolic (-9.3%) blood pressure were reduced, whereas maximal fat oxidation rate and VO2peak were significantly increased (38.9% and 8.0%, respectively; all P<.05). The remaining components of cardio-metabolic health measured (body weight, blood cholesterol, triglycerides, and glucose) were not changed after the intervention, and likewise, insulin sensitivity (CSi) remained unchanged. Total AMPK (23.4%), GLUT4 (20.5%), endothelial lipase (33.3%) protein expression, and citrate synthase activity (26.0%) increased with training (P<.05). Six months of AIT in MetS raises capacity for fat oxidation during exercise and increases VO2peak in combination with skeletal muscle improvements in mitochondrial enzyme activity. Muscle proteins involved in glucose, fat metabolism, and energy cell balance improved, although this was not reflected by parallel improvements in insulin sensitivity or blood lipid profile.

Football training over 5 years is associated with preserved femoral bone mineral density in men with prostate cancer.

This study investigated the association between long-term adherence to football training and retaining bone mineralization and physical capacity in men with prostate cancer (PCa) managed with androgen deprivation therapy (ADT). Patients completing follow-up at 32 weeks in the FC Prostate Randomized Controlled Trial (RCT) in 2012 or 2013 were invited to 5-year follow-up assessments in May 2017 (n = 30). Changes in physiological outcomes over time between the football participants (FTG) and nonparticipants (CON) were examined. Twenty-two men accepted the invitation of which 11, aged 71.3 ± 3.8 years, had continued to play self-organized football 1.7 (SD 0.5) times per week for 4½ years (±8 months). At 5 years, right femoral neck bone mineral density (BMD) had improved significantly in the FTG compared to CON (P = .028). No other significant between-group differences were observed. In FTG, RHR decreased by 4.3 bpm (P = .009) with no changes in CON. Muscle mass, knee-extensor muscle strength, VO2 max, and postural balance decreased in both groups. In FTG, the fraction of training time with HR between 80%-90% or >90% of HRmax was 29.9% (SD 20.6) and 22.8% (SD 28.7), respectively. Average distance covered during 3 × 20 minutes of football training was 2524 m (SD 525). Football training over a 5-year period was associated with preserved femoral neck BMD in elderly men with PCa managed on ADT. Intensity during football training was >80% of HRmax for 51% of training time after 5 years. Body composition and physical capacity deteriorated over 5 years regardless of football participation.

The effect of age and unilateral leg immobilization for 2 weeks on substrate utilization during moderate-intensity exercise in human skeletal muscle.

KEY POINTS: This study aimed to provide molecular insight into the differential effects of age and physical inactivity on the regulation of substrate metabolism during moderate-intensity exercise. Using the arteriovenous balance technique, we studied the effect of immobilization of one leg for 2 weeks on leg substrate utilization in young and older men during two-legged dynamic knee-extensor moderate-intensity exercise, as well as changes in key proteins in muscle metabolism before and after exercise. Age and immobilization did not affect relative carbohydrate and fat utilization during exercise, but the older men had higher uptake of exogenous fatty acids, whereas the young men relied more on endogenous fatty acids during exercise. Using a combined whole-leg and molecular approach, we provide evidence that both age and physical inactivity result in intramuscular lipid accumulation, but this occurs only in part through the same mechanisms. ABSTRACT: Age and inactivity have been associated with intramuscular triglyceride (IMTG) accumulation. Here, we attempt to disentangle these factors by studying the effect of 2 weeks of unilateral leg immobilization on substrate utilization across the legs during moderate-intensity exercise in young (n = 17; 23 ± 1 years old) and older men (n = 15; 68 ± 1 years old), while the contralateral leg served as the control. After immobilization, the participants performed two-legged isolated knee-extensor exercise at 20 ± 1 W (∼50% maximal work capacity) for 45 min with catheters inserted in the brachial artery and both femoral veins. Biopsy samples obtained from vastus lateralis muscles of both legs before and after exercise were used for analysis of substrates, protein content and enzyme activities. During exercise, leg substrate utilization (respiratory quotient) did not differ between groups or legs. Leg fatty acid uptake was greater in older than in young men, and although young men demonstrated net leg glycerol release during exercise, older men showed net glycerol uptake. At baseline, IMTG, muscle pyruvate dehydrogenase complex activity and the protein content of adipose triglyceride lipase, acetyl-CoA carboxylase 2 and AMP-activated protein kinase (AMPK)γ3 were higher in young than in older men. Furthermore, adipose triglyceride lipase, plasma membrane-associated fatty acid binding protein and AMPKγ3 subunit protein contents were lower and IMTG was higher in the immobilized than the contralateral leg in young and older men. Thus, immobilization and age did not affect substrate choice (respiratory quotient) during moderate exercise, but the whole-leg and molecular differences in fatty acid mobilization could explain the age- and immobilization-induced IMTG accumulation.

Cardiorespiratory fitness in 16 025 adults aged 18-91 years and associations with physical activity and sitting time.

Our aim was to provide up-to-date cardiorespiratory fitness reference data for adults of all ages and to investigate associations between cardiores-piratory fitness and leisure time physical activity as well as sitting time. In the Danish Health Examination Survey 2007-2008, cardiorespiratory fitness was estimated in 16 025 individuals aged 18-91 years from validated cycle ergometer exercise tests. Level of leisure time physical activity (sedentary, light, moderate, and vigorous) and daily sitting time in hours was obtained from a self-administered questionnaire. Men had 20-33% higher cardiorespiratory fitness than women, depending on age, and cardiorespiratory fitness decreased by 0.26 and 0.23 mL/min/kg per year in men and women, respectively. Cardiorespiratory fitness was higher among participants who reported a high level of physical activity in leisure time compared with participants who were sedentary. Among sedentary or lightly physically active participants, inverse associations between total daily sitting time and cardiorespiratory fitness were found, while there was no association between sitting time and cardiorespiratory fitness among moderately or vigorously physically active participants. These data on cardiorespiratory fitness can serve as useful reference material. Although reluctant to conclude on causality, sitting time might impact cardiorespiratory fitness among individuals with low levels of leisure time physical activity.

Increased post-operative cardiopulmonary fitness in gastric bypass patients is explained by weight loss.

Roux-en-Y gastric bypass (RYGB) leads to a major weight loss in obese patients. However, given that most patients remain obese after the weight loss, regular exercise should be part of a healthier lifestyle. The primary aim of this study was to investigate the cardiopulmonary fitness in obese patients before and after RYGB. Thirty-four patients had body composition and cardiopulmonary fitness (VO2max ) assessed and completed questionnaires regarding physical activity and function twice before RYGB (time points A and B) and 4 and 18 months after surgery (time points C and D). Weight loss was 37 ± 2 kg during the study period. VO2max increased (A: 21 ± 1 vs D: 29 mL/min/kg, P < 0.001), but absolute VO2max decreased (A: 2713 ± 126 vs 2609 ± 187 mL/min, P = 0.02) and VO2max per kilogram fat free mass did not change. Self-perceived limitations to perform exercise decreased and self-perceived physical fitness increased after RYGB. Self-reported low- and high-intensity physical activity did not change. With weight loss, self-rated fitness level increased and the limitations to perform exercise decreased in RYGB patients. Nevertheless, as shown by the lower absolute VO2max , RYGB patients do not adopt new exercise habits following surgery.

Central and peripheral hemodynamics in exercising humans: leg vs arm exercise.

In humans, arm exercise is known to elicit larger increases in arterial blood pressure (BP) than leg exercise. However, the precise regulation of regional vascular conductances (VC) for the distribution of cardiac output with exercise intensity remains unknown. Hemodynamic responses were assessed during incremental upright arm cranking (AC) and leg pedalling (LP) to exhaustion (Wmax) in nine males. Systemic VC, peak cardiac output (Qpeak) (indocyanine green) and stroke volume (SV) were 18%, 23%, and 20% lower during AC than LP. The mean BP, the rate-pressure product and the associated myocardial oxygen demand were 22%, 12%, and 14% higher, respectively, during maximal AC than LP. Trunk VC was reduced to similar values at Wmax. At Wmax, muscle mass-normalized VC and fractional O2 extraction were lower in the arm than the leg muscles. However, this was compensated for during AC by raising perfusion pressure to increase O2 delivery, allowing a similar peak VO2 per kg of muscle mass in both extremities. In summary, despite a lower Qpeak during arm cranking the cardiovascular strain is much higher than during leg pedalling. The adjustments of regional conductances during incremental exercise to exhaustion depend mostly on the relative intensity of exercise and are limb-specific.

The effect of high-intensity training on mitochondrial fat oxidation in skeletal muscle and subcutaneous adipose tissue.

High-intensity interval training (HIT) is known to increase mitochondrial content in a similar way as endurance training [60-90% of maximal oxygen uptake (VO2peak)]. Whether HIT increases the mitochondria's ability to oxidize lipids is currently debated. We investigated the effect of HIT on mitochondrial fat oxidation in skeletal muscle and adipose tissue. Mitochondrial oxidative phosphorylation (OXPHOS) capacity, mitochondrial substrate sensitivity (K(m)(app)), and mitochondrial content were measured in skeletal muscle and adipose tissue in healthy overweight subjects before and after 6 weeks of HIT (three times per week at 298 ± 21 W). HIT significantly increased VO2peak from 2.9 ± 0.2 to 3.1 ± 0.2 L/min. No differences were seen in maximal fat oxidation in either skeletal muscle or adipose tissue. K(m)(app) for octanoyl carnitine or palmitoyl carnitine were similar after training in skeletal muscle and adipose tissue. Maximal OXPHOS capacity with complex I- and II-linked substrates was increased after training in skeletal muscle but not in adipose tissue. In conclusion, 6 weeks of HIT increased VO2peak. Mitochondrial content and mitochondrial OXPHOS capacity were increased in skeletal muscle, but not in adipose tissue. Furthermore, mitochondrial fat oxidation was not improved in either skeletal muscle or adipose tissue.

Mitochondrial coupling and capacity of oxidative phosphorylation in skeletal muscle of Inuit and Caucasians in the arctic winter.

During evolution, mitochondrial DNA haplogroups of arctic populations may have been selected for lower coupling of mitochondrial respiration to ATP production in favor of higher heat production. We show that mitochondrial coupling in skeletal muscle of traditional and westernized Inuit habituating northern Greenland is identical to Danes of western Europe haplogroups. Biochemical coupling efficiency was preserved across variations in diet, muscle fiber type, and uncoupling protein-3 content. Mitochondrial phenotype displayed plasticity in relation to lifestyle and environment. Untrained Inuit and Danes had identical capacities to oxidize fat substrate in arm muscle, which increased in Danes during the 42 days of acclimation to exercise, approaching the higher level of the Inuit hunters. A common pattern emerges of mitochondrial acclimatization and evolutionary adaptation in humans at high latitude and high altitude where economy of locomotion may be optimized by preservation of biochemical coupling efficiency at modest mitochondrial density, when submaximum performance is uncoupled from VO2max and maximum capacities of oxidative phosphorylation.

Maintained peak leg and pulmonary VO2 despite substantial reduction in muscle mitochondrial capacity.

We recently reported the circulatory and muscle oxidative capacities of the arm after prolonged low-intensity skiing in the arctic (Boushel et al., 2014). In the present study, leg VO2 was measured by the Fick method during leg cycling while muscle mitochondrial capacity was examined on a biopsy of the vastus lateralis in healthy volunteers (7 male, 2 female) before and after 42 days of skiing at 60% HR max. Peak pulmonary VO2 (3.52 ± 0.18 L.min(-1) pre vs 3.52 ± 0.19 post) and VO2 across the leg (2.8 ± 0.4L.min(-1) pre vs 3.0 ± 0.2 post) were unchanged after the ski journey. Peak leg O2 delivery (3.6 ± 0.2 L.min(-1) pre vs 3.8 ± 0.4 post), O2 extraction (82 ± 1% pre vs 83 ± 1 post), and muscle capillaries per mm(2) (576 ± 17 pre vs 612 ± 28 post) were also unchanged; however, leg muscle mitochondrial OXPHOS capacity was reduced (90 ± 3 pmol.sec(-1) .mg(-1) pre vs 70 ± 2 post, P < 0.05) as was citrate synthase activity (40 ± 3 µmol.min(-1) .g(-1) pre vs 34 ± 3 vs P < 0.05). These findings indicate that peak muscle VO2 can be sustained with a substantial reduction in mitochondrial OXPHOS capacity. This is achieved at a similar O2 delivery and a higher relative ADP-stimulated mitochondrial respiration at a higher mitochondrial p50. These findings support the concept that muscle mitochondrial respiration is submaximal at VO2max , and that mitochondrial volume can be downregulated by chronic energy demand.

A maximal cycle test with good validity and high repeatability in adults of all ages.

In 11 680 individuals (18-85 years) maximal oxygen consumption (VO2max) was estimated indirectly in a maximal cycle test using a prediction model developed in a young population (15-28 years). A subsample of 182 individuals (23-77 years) underwent 2 maximal cycle tests with VO2max estimated indirectly in both tests and measured directly in one test. Agreement between the direct measurement and the indirect estimate of VO2max and repeatability of the indirect estimates of VO2max were examined by Bland-Altman plots, limits of agreement (LOA) and coefficient of repeatability (CR). The indirect method (mean VO2max=3 132 ml · min(-1)) underestimated VO2max as compared to the direct method (mean VO2max=3 190 ml · min(-1)) in men (bias: 58 ml · min(-1) (95% LOA-450 and 565)) and overestimated VO2max in women (mean VO2max=2 328 vs. 2 258 ml · min(-1), bias: - 70 ml · min(-1) (95% LOA-468 and 328)). The mean difference between the 2 indirect estimates was non-significant (men: - 11.9 ml · min(-1), women: 18.3 ml · min(-1)) with a CR of 279 ml · min(-1) (8.9%) in men and 274 ml · min(-1) (11.7%) in women. The validity of the indirect method was good despite minor sex-specific bias. Owing to this bias we suggest a new prediction model of VO2max. The maximal cycle test was highly repeatable.

Metabolic flexibility in postmenopausal women: Hormone replacement therapy is associated with higher mitochondrial content, respiratory capacity, and lower total fat mass.

AIM: To investigate effects of hormone replacement therapy in postmenopausal women on factors associated with metabolic flexibility related to whole-body parameters including fat oxidation, resting energy expenditure, body composition and plasma concentrations of fatty acids, glucose, insulin, cortisol, and lipids, and for the mitochondrial level, including mitochondrial content, respiratory capacity, efficiency, and hydrogen peroxide emission. METHODS: 22 postmenopausal women were included. 11 were undergoing estradiol and progestin treatment (HT), and 11 were matched non-treated controls (CONT). Peak oxygen consumption, maximal fat oxidation, glycated hemoglobin, body composition, and resting energy expenditure were measured. Blood samples were collected at rest and during 45 min of ergometer exercise (65% VO2peak). Muscle biopsies were obtained at rest and immediately post-exercise. Mitochondrial respiratory capacity, efficiency, and hydrogen peroxide emission in permeabilized fibers and isolated mitochondria were measured, and citrate synthase (CS) and 3-hydroxyacyl-CoA dehydrogenase (HAD) activity were assessed. RESULTS: HT showed higher absolute mitochondrial respiratory capacity and post-exercise hydrogen peroxide emission in permeabilized fibers and higher CS and HAD activities. All respiration normalized to CS activity showed no significant group differences in permeabilized fibers or isolated mitochondria. There were no differences in resting energy expenditure, maximal, and resting fat oxidation or plasma markers. HT had significantly lower visceral and total fat mass compared to CONT. CONCLUSION: Use of hormone therapy is associated with higher mitochondrial content and respiratory capacity and a lower visceral and total fat mass. Resting energy expenditure and fat oxidation did not differ between HT and CONT.

Metformin-treated patients with type 2 diabetes have normal mitochondrial complex I respiration.

AIMS/HYPOTHESIS: The glucose-lowering drug metformin has been shown to inhibit complex I of the mitochondrial electron transport chain in skeletal muscle. To investigate this effect in vivo we studied skeletal muscle mitochondrial respiratory capacity and content from patients with type 2 diabetes treated with metformin (n = 14) or sulfonylurea (n = 8) and healthy control (n = 18) participants. METHODS: Mitochondrial respiratory capacity was measured ex vivo in permeabilised muscle fibres obtained from the vastus lateralis muscle of all participants. The respiratory response to in vitro titration with metformin was measured in controls. Citrate synthase (CS) activity, and fasting plasma glucose, insulin and HbA(1c) levels were measured and body composition was determined. RESULTS: Participants were matched for age, BMI and percentage body fat. Fasting plasma glucose concentrations were higher (p < 0.05) in those treated with sulfonylureas and metformin than in controls. CS activity was comparable between metformin-treated and control participants, but tended to be lower in those receiving sulfonylureas. Mitochondrial respiratory capacity with substrates for complex I and complex I and II was comparable in the groups, both when estimated per mg of tissue and when normalised to CS activity. In vitro metformin titration demonstrated a dose-dependent inhibitory effect on complex I and II in human skeletal muscle at suprapharmacological concentrations. CONCLUSIONS/INTERPRETATION: Metformin treatment does not inhibit mitochondrial complex I respiration in the electron transport chain in human skeletal muscle of patients with type 2 diabetes when measured ex vivo. Inhibition of complex I and II respiration in controls was demonstrated by metformin titration in vitro at doses well above those observed during metformin treatment.

Muscle ceramide content is similar after 3 weeks' consumption of fat or carbohydrate diet in a crossover design in patients with type 2 diabetes.

This study aimed at investigating the effect of prolonged adaptation to fat- or carbohydrate-rich diet on muscle ceramide in type 2 diabetes patients, using a longitudinal crossover study. Eleven type 2 diabetes patients consumed isocaloric fat- or carbohydrate-rich diet for 3 weeks in random order. After each dietary intervention period, muscle glycogen, triacylglycerol and ceramide content and plasma concentrations of insulin, adiponectin, glucose and FFA were determined. Insulin resistance was assessed by HOMA2 calculation. After the dietary period, plasma glucose and insulin, insulin sensitivity, muscle glycogen, triacylglycerol and ceramide content were similar. Plasma adiponectin concentration was significantly higher after fat compared with carbohydrate-rich diet. Results indicated that following fat-rich diet intake muscle ceramide and triacylglycerol concentrations were not different compared with that after carbohydrate-rich diet. Furthermore, plasma adiponectin concentration was higher after fat-rich compared with carbohydrate-rich diet, but insulin sensitivity remained similar despite the major difference in dietary macronutrient composition.

Cryopreservation of human skeletal muscle impairs mitochondrial function.

Previous studies have investigated if cryopreservation is a viable approach for functional mitochondrial analysis. Different tissues have been studied, and conflicting results have been published. The aim of the present study was to investigate if mitochondria in human skeletal muscle maintain functionality after long term cryopreservation (1 year). Skeletal muscle samples were preserved in dimethyl sulfoxide (DMSO) for later analysis. Human skeletal muscle fibres were thawed and permeabilised with saponin, and mitochondrial respiration was measured by high-resolution respirometry. The capacity of oxidative phosphorylation was significantly (P < 0.05) reduced in cryopreserved human skeletal muscle samples. Cryopreservation impaired respiration with substrates linked to Complex I more than for Complex II (P < 0.05). Addition of cytochrome c revealed an increase in respiration indicating cytochrome c loss from the mitochondria. The results from this study demonstrate that normal mitochondrial functionality is not maintained in cryopreserved human skeletal muscle samples.

Increased mitochondrial substrate sensitivity in skeletal muscle of patients with type 2 diabetes.

AIMS/HYPOTHESIS: Mitochondrial respiration has been linked to insulin resistance. We studied mitochondrial respiratory capacity and substrate sensitivity in patients with type 2 diabetes (patients), and obese and lean control participants. METHODS: Mitochondrial respiration was measured in permeabilised muscle fibres by respirometry. Protocols for respirometry included titration of substrates for complex I (glutamate), complex II (succinate) and both (octanoyl-carnitine). Myosin heavy chain (MHC) composition, antioxidant capacity (manganese superoxide dismutase [MnSOD]), citrate synthase activity and maximal oxygen uptake (VO2) were also determined. Insulin sensitivity was determined with the isoglycaemic-hyperinsulinaemic clamp technique. RESULTS: Insulin sensitivity was different (p < 0.05) between the groups (patients

Normal mitochondrial function and increased fat oxidation capacity in leg and arm muscles in obese humans.

AIM/HYPOTHESIS: The aim of this study was to investigate mitochondrial function, fibre-type distribution and substrate oxidation during exercise in arm and leg muscles in male postobese (PO), obese (O) and age- and body mass index (BMI)-matched control (C) subjects. The hypothesis of the study was that fat oxidation during exercise might be differentially preserved in leg and arm muscles after weight loss. METHODS: Indirect calorimetry was used to calculate fat and carbohydrate oxidation during both progressive arm-cranking and leg-cycling exercises. Muscle biopsy samples were obtained from musculus deltoideus (m. deltoideus) and m. vastus lateralis muscles. Fibre-type composition, enzyme activity and O(2) flux capacity of saponin-permeabilized muscle fibres were measured, the latter by high-resolution respirometry. RESULTS: During the graded exercise tests, peak fat oxidation during leg cycling and the relative workload at which it occurred (FatMax) were higher in PO and O than in C. During arm cranking, peak fat oxidation was higher in O than in C, and FatMax was higher in O than in PO and C. Similar fibre-type composition was found between groups. Plasma adiponectin was higher in PO than in C and O, and plasma leptin was higher in O than in PO and C. CONCLUSIONS: In O subjects, maximal fat oxidation during exercise and the eliciting relative exercise intensity are increased. This is associated with higher intramuscular triglyceride levels and higher resting non esterified fatty acid (NEFA) concentrations, but not with differences in fibre-type composition, mitochondrial function or muscle enzyme levels compared with Cs. In PO subjects, the changes in fat oxidation are preserved during leg, but not during arm, exercise.