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.

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.

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.

Alpine Skiing With total knee ArthroPlasty (ASWAP): study design and intervention.

The aim of this study was to monitor the long-term effects of skiing on health-related parameters and implant related factors like loosening and wear in patients with total knee arthroplasty. This paper describes the overall study design, general demographics, and physiological demand of the intervention phase. A control group design consisting of an intervention group (n = 14; age: 70.4 ± 4.5 years) and a control group (n = 17; age: 71.5 ± 5.1 years) was utilized in this study. Parameters of interest were measured during pre-, post-, and retention test sessions. During the 12 weeks of intervention, an average of 25.5 days of guided skiing was conducted by each patient. Daily heart rate (HR) profiles and global positioning system data throughout the ski day were recorded. The intervention group completed an average of 3393 vertical meters of downhill skiing, with a total skiing distance of 33.6 km/day. Average skiing speed was 8.2 m/s. In the skiing phase, the average physiological load was 75.9 ± 6.6% of HRmax . Further effects of the 12-week skiing intervention on the tested parameters will be reported in the following papers of this supplementum.

Alpine Skiing With total knee ArthroPlasty (ASWAP): impact on molecular and architectural features of musculo-skeletal ageing.

This study investigated features of skeletal muscle ageing in elderly individuals having previously undergone unilateral total knee arthroplasty (TKA) and whether markers of sarcopenia could be mitigated by a 12-week alpine skiing intervention. Novel biomarkers agrin, indicative of neuromuscular junction (NMJ) degeneration, tumor suppressor protein p53, associated with muscle atrophy, and a new ultrasound-based muscle architecture biomarker were used to characterize sarcopenia. Participant details and study design are presented by Kösters et al. (2015). The results of this study show that NMJ degeneration is widespread among active septuagenarians previously subjected to TKA: all participants showed elevated agrin levels upon recruitment. At least 50% of individuals were identified as sarcopenic based on their muscle architecture, supporting the hypothesis that NMJ alterations precede sarcopenia. Notably, sarcopenia was strongly associated with the expression of p53, which seems to confirm its validity as a biomarker of muscle atrophy. Training did not significantly modify any of these biomarkers. In view of the lack of accretion of muscle mass in response to the alpine skiing intervention, we hypothesize that local muscle inflammation and oxidative stress may have blunted the anabolic response to training and promoted muscle breakdown in this elderly post-TKA population.

Alpine Skiing With total knee ArthroPlasty (ASWAP): metabolism, inflammation, and skeletal muscle fiber characteristics.

We investigated the effect of alpine skiing for 12 weeks on skeletal muscle characteristics and biomarkers of glucose homeostasis and cardiovascular risk factors. Twenty-three patients with a total knee arthroplasty (TKA) were studied 2.9 ± 0.9 years (mean ± SD) after the operation. Fourteen patients participated in the intervention group (IG) and nine in the control group (CG). Blood samples and muscle biopsies were obtained before (PRE) and 7.3 ± 0.8 days after (POST) the intervention, and blood samples again after a retention (RET) phase of 8 weeks. With skiing, glucose homeostasis improved in IG (decrease in fasting insulin, increase in muscle glycogen) but not in CG. Fiber type distribution and size, as well as capillary density and number of capillaries around the fibers (CAF), were not different between the operated and the non-operated leg in either group. The relative number of type I fibers increased with skiing in IG with no change in CG. Inflammatory biomarkers, plasma lipids, and mitochondrial proteins and activity did not change. Alpine skiing is metabolically beneficial and can be used as a training modality by elderly people with TKA.

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.

Adjustments of muscle capillarity but not mitochondrial protein with skiing in the elderly.

Downhill skiing in the elderly increases maximal oxygen uptake (VO2max) and carbohydrate handling, and produces muscle hypertrophy. We hypothesized that adjustments of the cellular components of aerobic glucose combustion in knee extensor muscle, and cardiovascular adjustments, would increase in proportion to VO2max. Nineteen healthy elderly subjects (age 67.5 ± 2.9 years) who completed 28.5 days of guided downhill skiing over 3 months were assessed for anthropometric variables, cardiovascular parameters (heart rate, hematocrit), VO2max, and compared with controls (n = 20). Biopsies of vastus lateralis muscle were analyzed for capillary density and expression of respiratory chain markers (NDUFA9, SDHA, UQCRC1, ATP5A1) and the glucose transporter GLUT4. Statistical significance was assessed with a repeated analysis of variance and Fisher's post-hoc test at a P value of 5%. VO2max increased selectively with ski training (+7 ± 2%). Capillary density (+11 ± 5%) and capillary-to-fiber ratio (12 ± 5%), but not the concentration of metabolic proteins, in vastus lateralis were increased after skiing. Cardiovascular parameters did not change. Fold changes in VO2max and capillary-to-fiber ratio were correlated and were under genetic control by polymorphisms of the regulator of vascular tone, angiotensin converting enzyme. The observations indicate that increased VO2max after recreational downhill ski training is associated with improved capillarity in a mainly recruited muscle group.

Glucose-dependent insulinotropic polypeptide has impaired effect on abdominal, subcutaneous adipose tissue metabolism in obese subjects.

OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) appears to have a role in lipid metabolism. Recently, we showed that GIP in combination with hyperinsulinemia and hyperglycemia increases triglyceride uptake in abdominal, subcutaneous adipose tissue in lean humans. It has been suggested that increased GIP secretion in obesity will promote lipid deposition in adipose tissue. In light of the current attempts to employ GIP antagonists in the treatment and prevention of human obesity, the present experiments were performed in order to elucidate whether the adipose tissue lipid metabolism would be enhanced or blunted during a GIP, hyperinsulinemic and hyperglycemic (HI-HG) clamp in obese subjects with either normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). DESIGN: Sixteen obese (BMI>30 kg m(-2)) subjects were divided into two groups, based on their plasma glucose response to an oral glucose challenge: (i) NGT and (ii) IGT. Abdominal, subcutaneous adipose tissue lipid metabolism was studied by conducting measurements of arteriovenous concentrations of metabolites and regional adipose tissue blood flow (ATBF) during GIP (1.5 pmol kg(-1) min(-1)) in combination with a HI-HG clamp. RESULTS: In both groups, ATBF responses were significantly lower than what we have found previously in healthy, lean subjects (P<0.0001). The flow response was significantly lower in the IGT group than in the NGT group (P=0.03). It was not possible to show any increase in the lipid deposition in adipose tissue under the applied experimental conditions and likewise the circulating triglyceride (TAG) concentrations remained constant. CONCLUSION: The applied GIP, HI-HG clamp did not induce any changes in TAG uptake in adipose tissue in obese subjects. This may be due to a blunted increase in ATBF. These experiments therefore suggest that GIP does not have a major role in postprandial lipid metabolism in obese subjects.

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.

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

The effect of rowing on endothelial function and insulin action in healthy controls and in patients with type 2 diabetes.

Patients with type 2 diabetes (T2DM) have an increased risk for cardiovascular disease. We examined the effects of 8 weeks of home-based rowing training (heart rate corresponding to 65-70% of VO(2 peak) ) on endothelial function and glucose clearance (local and systemic effects) in male subjects with T2DM (n=9) and matched controls (n=8). Before and after training (30 min every other day), all subjects underwent sequential graded brachial artery infusions of non-insulin vasodilators (acetylcholine; sodium nitroprusside; adenosine). Forearm blood flow was improved by training in controls (without and with insulin: P=0.003 and 0.05, respectively) but not in subjects with T2DM. Likewise, whole body glucose clearance increased in response to training in controls (P=0.05) but not in T2DM. However, in both groups, the capacity for local forearm glucose extraction (controls: P=0.001; T2DM: P=0.002) and clearance (controls: P<0.001; T2DM: P=0.01) were positively affected by exercise. While the subjects with T2DM did not respond to the same degree as controls to 8 weeks of home-based exercise, there are clear benefits as illustrated by improvements in local glucose disposal. Training of higher intensity or duration may be required in order to elicit a response similar to controls.

Salzburg Skiing for the Elderly Study: changes in cardiovascular risk factors through skiing in the elderly.

Numerous studies have shown that treatment of the modifiable cardiovascular risk factors (CVRF) results in a decreased risk to suffer from stroke or myocardial infarction. Despite the fact that exercise training is a potent treatment choice for CVRF, this is the first randomized study to assess the effects of alpine skiing on CVRF in elderly skiers. Subjects (n=42) were randomized into an intervention group (IG; n=22; 12 males/10 females; age: 66.6 ± 2.1 years) completing 12 weeks of guided skiing or a control group (CG; n=20; 10 males/10 females; age: 67.3 ± 4.4 years). CVRF were assessed before and after the intervention period. No cardiovascular event occurred within a total of 795.1 h of skiing. A significant increase in exercise capacity in IG (ΔVO(2 max) : +2.0 mL/kg/min, P=0.005) but not in CG (ΔVO(2 max) : -0.1 mL/kg/min, P=0.858; IG vs CG: P=0.008) as well as a decrease in body fat mass [IG: -2.3%, P<0.0001; CG: ± 0.0%, P=0.866; IG vs CG: P<0.0001] was achieved. Blood pressure, blood lipids, heart rate and everyday physical activity remained essentially unchanged. Alpine skiing in the elderly is safe with respect to cardiovascular events, and improves some, but not all CVRF.

Glucose homeostasis and cardiovascular disease biomarkers in older alpine skiers.

Alpine skiing and ski training involves elements of static and dynamic training, and may therefore improve insulin sensitivity. Healthy men and women who where beginners/intermediate level of alpine skiing, were studied before (Pre) and immediately after (Post) 12 weeks of alpine ski training. After an additional 8 weeks a third test (retention study, Ret) was performed. The subjects were randomized into an intervention group (IG, n=22, age=66.6 ± 0.4 years) or a control group (CG, n=20, age=67.0 ± 1.0 years). Plasma glucose decreased (P<0.05) in CG, but increased (P<0.05) again at Ret, while a continued decrease was seen in IG (Ret vs Post, P<0.05). Plasma insulin decreased (P<0.05) with training in IG, while no effect was seen in CG. HOMA2 index for insulin resistance decreased (P<0.05) from 0.80 ± 0.08 to 0.71 ± 0.09 in IG. The value at Ret (0.57 ± 0.08) tended (P=0.067) to be different from Post. In CG the corresponding values were 0.84 ± 0.09, 0.81 ± 0.12 and 0.70 ± 0.09, respectively. Total cholesterol and LDL decreased in both IC and CG, a result, interpreted as seasonal variation. Biomarkers for endothelial function and low-grade inflammation were not elevated and similar in IG and CG, and did not change. Alpine ski training improves glucose homeostasis and insulin sensitivity in healthy, elderly individuals.

The influence of age, sex and cardiorespiratory fitness on maximal fat oxidation rate.

Fat oxidation decreases with age, yet no studies have previously investigated if aging affects the maximal fat oxidation rate (MFO) during exercise in men and women differently. We hypothesized that increased age would be associated with a decline in MFO and this would be more pronounced in women due to menopause, compared with men. In this cross-sectional study design, 435 (247/188, male/female) subjects of varying ages performed a DXA scan, a submaximal graded exercise test and a maximal oxygen uptake test, to measure MFO and cardiorespiratory fitness (CRF) by indirect calorimetry. Subjects were stratified into 12 groups according to sex (male/female), age (<45, 45-55 and >55 years), CRF (below average and above average). Women aged <45 years had a higher MFO relative to fat free mass (FFM) (mg/min/kg) compared with men, regardless of CRF. However, there were no differences in MFO (mg/min/kg FFM) between men and women, in the groups aged between 45-55 and >55 years. In summary, we found that women aged <45 years display a higher MFO (mg/min/kg FFM) compared with men and that this sexual divergence is abolished after the age of 45 years. Novelty: Maximal fat oxidation rate is higher in young women compared with men. This sex-related difference is attenuated after the age of 45 years. Cardiorespiratory fitness does not influence this sex-related difference.

Effect of physical training on mitochondrial respiration and reactive oxygen species release in skeletal muscle in patients with obesity and type 2 diabetes.

AIM/HYPOTHESIS: Studies have suggested a link between insulin resistance and mitochondrial dysfunction in skeletal muscles. Our primary aim was to investigate the effect of aerobic training on mitochondrial respiration and mitochondrial reactive oxygen species (ROS) release in skeletal muscle of obese participants with and without type 2 diabetes. METHODS: Type 2 diabetic men (n = 13) and control (n = 14) participants matched for age, BMI and physical activity completed 10 weeks of aerobic training. Pre- and post-training muscle biopsies were obtained before a euglycaemic-hyperinsulinaemic clamp and used for measurement of respiratory function and ROS release in isolated mitochondria. RESULTS: Training significantly increased insulin sensitivity, maximal oxygen consumption and muscle mitochondrial respiration with no difference between groups. When expressed in relation to a marker of mitochondrial density (intrinsic mitochondrial respiration), training resulted in increased mitochondrial ADP-stimulated respiration (with NADH-generating substrates) and decreased respiration without ADP. Intrinsic mitochondrial respiration was not different between groups despite lower insulin sensitivity in type 2 diabetic participants. Mitochondrial ROS release tended to be higher in participants with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Aerobic training improves muscle respiration and intrinsic mitochondrial respiration in untrained obese participants with and without type 2 diabetes. These adaptations demonstrate an increased metabolic fitness, but do not seem to be directly related to training-induced changes in insulin sensitivity.

Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men.

Physical inactivity is a risk factor for insulin resistance. We examined the effect of 9 days of bed rest on basal and insulin-stimulated expression of genes potentially involved in insulin action by applying hypothesis-generating microarray in parallel with candidate gene real-time PCR approaches in 20 healthy young men. Furthermore, we investigated whether bed rest affected DNA methylation in the promoter region of the peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1A) gene. Subjects were reexamined after 4 wk of retraining. We found that bed rest induced insulin resistance and altered the expression of more than 4,500 genes. These changes were only partly normalized after 4 wk of retraining. Pathway analyses revealed significant downregulation of 34 pathways, predominantly those of genes associated with mitochondrial function, including PPARGC1A. Despite induction of insulin resistance, bed rest resulted in a paradoxically increased response to acute insulin stimulation in the general expression of genes, particularly those involved in inflammation and endoplasmatic reticulum (ER) stress. Furthermore, bed rest changed gene expressions of several insulin resistance and diabetes candidate genes. We also observed a trend toward increased PPARGC1A DNA methylation after bed rest. We conclude that impaired expression of PPARGC1A and other genes involved in mitochondrial function as well as a paradoxically increased response to insulin of genes involved in inflammation and ER stress may contribute to the development of insulin resistance induced by bed rest. Lack of complete normalization of changes after 4 wk of retraining underscores the importance of maintaining a minimum of daily physical activity.

Increased rate of whole body lipolysis before and after 9 days of bed rest in healthy young men born with low birth weight.

Individuals born with low birth weight (LBW) are at risk of developing type 2 diabetes mellitus (T2D), which may be precipitated by physical inactivity. Twenty-two LBW subjects and twenty-three controls were studied before and after bed rest by the hyperinsulinemic euglycemic clamp combined with indirect calorimetry and infusion of stable isotope tracers and preceded by an intravenous glucose tolerance test. LBW subjects had a similar body mass index but elevated abdominal obesity compared with controls. The basal rate of whole body lipolysis (WBL) was elevated in LBW subjects with and without correction for abdominal obesity before and after bed rest (all P = 0.01). Skeletal muscle hormone-sensitive lipase (HSL) protein expression and phosphorylation at Ser565 were similar in the two groups. Bed rest resulted in a decrease in WBL and an increased skeletal muscle HSL Ser565 phosphorylation indicating a decreased HSL activity in both groups. All subjects developed peripheral insulin resistance in response to bed rest (all P < 0.0001) with no differences between groups. LBW subjects developed hepatic insulin resistance in response to bed rest. In conclusion, increased WBL may contribute to the development of hepatic insulin resistance when exposed to bed rest in LBW subjects. Nine days of bed rest causes severe peripheral insulin resistance and reduced WBL and skeletal muscle HSL activity, as well as a compensatory increased insulin secretion, with no differences in LBW subjects and controls.