Elevated heart rate and decreased muscle endothelial nitric oxide synthase in early development of insulin resistance.

Insulin resistance (IR) is a risk factor for the development of several major metabolic diseases. Muscle fiber composition is established early in life and is associated with insulin sensitivity. Hence, muscle fiber composition was used to identify early defects in the development of IR in healthy young individuals in the absence of clinical manifestations. Biopsies were obtained from the thigh muscle, followed by an intravenous glucose tolerance test. Indices of insulin action were calculated and cardiovascular measurements, analyses of blood and muscle were performed. Whole body insulin sensitivity (SIgalvin) was positively related to expression of type I muscle fibers (r = 0.49; P < 0.001) and negatively related to resting heart rate (HR, r = -0.39; P < 0.001), which was also negatively related to expression of type I muscle fibers (r = -0.41; P < 0.001). Muscle protein expression of endothelial nitric oxide synthase (eNOS), whose activation results in vasodilation, was measured in two subsets of subjects expressing a high percentage of type I fibers (59 ± 6%; HR = 57 ± 9 beats/min; SIgalvin = 1.8 ± 0.7 units) or low percentage of type I fibers (30 ± 6%; HR = 71 ± 11; SIgalvin = 0.8 ± 0.3 units; P < 0.001 for all variables vs. first group). eNOS expression was 1) higher in subjects with high type I expression; 2) almost twofold higher in pools of type I versus II fibers; 3) only detected in capillaries surrounding muscle fibers; and 4) linearly associated with SIgalvin. These data demonstrate that an altered function of the autonomic nervous system and a compromised capacity for vasodilation in the microvasculature occur early in the development of IR.NEW & NOTEWORTHY Insulin resistance (IR) is a risk factor for the development of several metabolic diseases. In healthy young individuals, an elevated heart rate (HR) correlates with low insulin sensitivity and high expression of type II skeletal muscle fibers, which express low levels of endothelial nitric oxide synthase (eNOS) and, hence, a limited capacity to induce vasodilation in response to insulin. Early targeting of the autonomic nervous system and microvasculature may attenuate development of diseases stemming from insulin resistance.

Effects of prolonged sitting and physical activity breaks on measures of arterial stiffness and cortisol in adolescents.

AIM: In adults, prolonged periods of sitting have been linked to acute negative effects on vascular structure and function. The aim of this study was to evaluate the acute effects of physical activity (PA) breaks during prolonged sitting on arterial stiffness, cortisol and psychological factors in adolescents. METHODS: Adolescents underwent different short (3-min) breaks starting every 20 min, during 80 min of sitting on three separate days. Breaks were (A) social seated breaks (SOC), (B) low-intensity simple resistance activity PA breaks (SRA) and (C) moderate-intensity step-up PA breaks (STEP). The arterial stiffness measures were augmentation index (AIx), AIx@75 and pulse wave velocity (PWV). Cortisol was measured from saliva. Psychological factors were self-reported. RESULTS: Eleven girls and six boys (average age 13.6 ± 0.7 years) participated, with average baseline heart rates of 72 ± 11 bpm, systolic/diastolic blood pressure 111 ± 7/64 ± 6 mmHg and cortisol 10.9 ± 5.8 nmoL/L. PWV, cortisol and psychological factors did not change after any of the conditions. AIx@75 increased significantly (4.9 ± 8.7-9.2 ± 13.2) after the STEP intervention compared with SOC and SRA (time × condition p < 0.05). CONCLUSION: Arterial stiffness increased after prolonged sitting with frequent, short step-up activity breaks. The results indicate potential important intensity-dependent effects of physical activity on vascular regulation in youth.

Insulin resistance after a 3-day fast is associated with an increased capacity of skeletal muscle to oxidize lipids.

There is a debate on whether lipid-mediated insulin resistance derives from an increased or decreased capacity of muscle to oxidize fats. Here, we examine the involvement of muscle fiber composition in the metabolic responses to a 3-day fast (starvation, which results in increases in plasma lipids and insulin resistance) in two groups of healthy young subjects: 1), area occupied by type I fibers = 61.0 ± 11.8%; 2), type I area = 36.0 ± 4.9% (P < 0.001). Muscle biopsies and intravenous glucose tolerance tests were performed after an overnight fast and after starvation. Biopsies were analyzed for muscle fiber composition and mitochondrial respiration. Indices of glucose tolerance and insulin sensitivity were determined. Glucose tolerance was similar in both groups after an overnight fast and deteriorated to a similar degree in both groups after starvation. In contrast, whole body insulin sensitivity decreased markedly after starvation in group 1 (P < 0.01), whereas the decrease in group 2 was substantially smaller (P = 0.06). Nonesterified fatty acids and ß-hydroxybutyrate levels in plasma after an overnight fast were similar between groups and increased markedly and comparably in both groups after starvation, demonstrating similar degrees of lipid load. The capacity of permeabilized muscle fibers to oxidize lipids was significantly higher in group 1 versus 2, whereas there was no significant difference in pyruvate oxidation between groups. The data demonstrate that loss of whole body insulin sensitivity after short-term starvation is a function of muscle fiber composition and is associated with an elevated rather than a diminished capacity of muscle to oxidize lipids.NEW & NOTEWORTHY Whether lipid-mediated insulin resistance occurs as a result of an increased or decreased capacity of skeletal muscle to oxidize lipids has been debated. We show that a 3-day fast results in increases in circulating lipids and insulin resistance in subjects expressing a high or low proportion of type I muscle fibers. High expression of type I is associated with a higher capacity to oxidize lipids and a greater loss of insulin sensitivity after starvation.

Reliability of the accelerometer to control the effects of physical activity in older adults.

BACKGROUND: Reliable physical activity measurements in community-dwelling older adults are important to determine effects of targeted health promotion interventions. Many exercise interventions aim to improve time spent sedentary (SED), in light-intensity-physical-activity (LPA) and moderate-to-vigorous-intensity-physical-activity (MVPA), since these parameters have independently proposed associations with health and longevity. However, many previous studies rely on self-reports which have lower validity compared to accelerometer measured physical activity patterns. In addition, separating intervention-effects from reactivity measurements requires sufficient test-retest reliability for accelerometer assessments, which is lacking in older adults. OBJECTIVES: The study objective was to investigate the reliability of sensor-based PA-patterns in community-dwelling older adults. Furthermore, to investigate change over time of physical activity patterns and examine any compensatory-effect from the eight-week supervised exercise-intervention. METHODS: An exercise-group (n = 78, age-range:65-91yrs) performed two 1h-exercise sessions/week during eight-weeks. PA-pattern was assessed (using hip-worn accelerometers), twice before and once during the last-week of the intervention. A control-group (n = 43, age-range:65-88yrs) performed one pre-test and the end-test with no exercise-intervention. A dependent-t-test, mean-difference (95%-CI), limits-of-agreement and intraclass-correlation-coefficient-ICC were used between the two pre-tests. Repeated-measures-ANOVA were used to analyze any intervention-effects. RESULTS: The exercise-groups´ two pre-tests showed generally no systematic change in any PA- or SED-parameter (ICC ranged 0.75-0.90). Compared to the control group, the exercise intervention significantly (time x group-interaction, p<0.05) increased total-PA-cpm (exercise-group/control-group +17%/+7%) and MVPA-min/week (+41/-2min) and decreased %-of-wear-time for SED-total (-4.7%/-2.7%) and SED-bouts (-5.7%/-1.8%), and SED-bouts min/d (-46/-16min). At baseline level, no significant differences were found between the two groups for any parameter. CONCLUSIONS: The current study presents a good test-retest-reliability of sensor-based-one-week-assessed-PA-pattern in older-adults. Participating in an 8-week supervised exercise intervention improved some physical activity and sedentary parameters compared to the control group. No compensatory-effect was noted in the intervention-group i.e., no decrease in any PA-parameter or increase in SED at End-test (in %-of-wear-time, min/day or total-PA).

Extreme Variations in Muscle Fiber Composition Enable Detection of Insulin Resistance and Excessive Insulin Secretion.

CONTEXT: Muscle fiber composition is associated with peripheral insulin action. OBJECTIVE: We investigated whether extreme differences in muscle fiber composition are associated with alterations in peripheral insulin action and secretion in young, healthy subjects who exhibit normal fasting glycemia and insulinemia. METHODS: Relaxation time following a tetanic contraction was used to identify subjects with a high or low expression of type I muscle fibers: group 1 (n = 11), area occupied by type I muscle fibers = 61.0 ± 11.8%, and group 2 (n = 8), type I area = 36.0 ± 4.9% (P < 0.001). Biopsies were obtained from the vastus lateralis muscle and analyzed for mitochondrial respiration on permeabilized fibers, muscle fiber composition, and capillary density. An intravenous glucose tolerance test was performed and indices of glucose tolerance, insulin sensitivity, and secretion were determined. RESULTS: Glucose tolerance was similar between groups, whereas whole-body insulin sensitivity was decreased by ~50% in group 2 vs group 1 (P = 0.019). First-phase insulin release (area under the insulin curve during 10 minutes after glucose infusion) was increased by almost 4-fold in group 2 vs group 1 (P = 0.01). Whole-body insulin sensitivity was correlated with percentage area occupied by type I fibers (r = 0.54; P = 0.018) and capillary density in muscle (r = 0.61; P = 0.005) but not with mitochondrial respiration. Insulin release was strongly related to percentage area occupied by type II fibers (r = 0.93; P < 0.001). CONCLUSIONS: Assessment of muscle contractile function in young healthy subjects may prove useful in identifying individuals with insulin resistance and enhanced glucose-stimulated insulin secretion prior to onset of clinical manifestations.

Increased autophagy signaling but not proteasome activity in human skeletal muscle after prolonged low-intensity exercise with negative energy balance.

Little is known about the molecular regulation of skeletal muscle protein turnover during exercise in field conditions where energy is intake inadequate. Here, 17 male and 7 female soldiers performed an 8 days long field-based military operation. Vastus lateralis muscle biopsies, in which autophagy, the ubiquitin-proteasome system, and the mTORC1 signaling pathway were studied, were collected before and after the operation. The 187 h long operation resulted in a 15% and 29% negative energy balance as well as a 4.1% and 4.6% loss of body mass in women and men, respectively. After the operation protein levels of ULK1 as well as the phosphorylation of ULK1Ser317 and ULK1Ser555 had increased by 11%, 39%, and 13%, respectively, and this was supported by a 17% increased phosphorylation of AMPKThr172 (P < 0.05). The LC3b-I/II ratio was threefold higher after compared to before the operation (P < 0.05), whereas protein levels of p62/SQSTM1 were unchanged. The ß1, ß2, and ß5 activity of the proteasome and protein levels of MAFbx did not change, whereas levels of MuRF-1 were slightly reduced (6%, P < 0.05). Protein levels and phosphorylation status of key components in the mTORC1 signaling pathway remained at basal levels after the operation. Muscle levels of glycogen decreased from 269 ± 12 to 181 ± 9 mmol·kg dry·muscle-1 after the exercise period (P < 0.05). In conclusion, the 8 days of field-based exercise resulted in induction of autophagy without any increase in proteasome activity or protein ubiquitination. Simultaneously, the regulation of protein synthesis through the mTORC1 signaling pathway was maintained.

Improving Strength, Power, Muscle Aerobic Capacity, and Glucose Tolerance through Short-term Progressive Strength Training Among Elderly People.

This protocol describes the simultaneous use of a broad span of methods to examine muscle aerobic capacity, glucose tolerance, strength, and power in elderly people performing short-term resistance training (RET). Supervised progressive resistance training for 1 h three times a week over 8 weeks was performed by RET participants (71±1 years, range 65-80). Compared to a control group without training, the RET showed improvements on the measures used to indicate strength, power, glucose tolerance, and several parameters of muscle aerobic capacity. Strength training was performed in a gym with only robust fitness equipment. An isokinetic dynamometer for knee extensor strength permitted the measurement of concentric, eccentric, and static strength, which increased for the RET group (8-12% post- versus pre-test). The power (rate of force development, RFD) at the initial 0-30 ms also showed an increase for the RET group (52%). A glucose tolerance test with frequent blood glucose measurements showed improvements only for the RET group in terms of blood glucose values after 2 h (14%) and the area under the curve (21%). The blood lipid profile also improved (8%). From muscle biopsy samples prepared using histochemistry, the amount of fiber type IIa increased, and a trend towards a decrease in IIx in the RET group reflected a change to a more oxidative profile in terms of fiber composition. Western blot (to determine the protein content related to the signaling for muscle protein synthesis) showed a rise of 69% in both Akt and mTOR in the RET group; this also showed an increase in mitochondrial proteins for OXPHOS complex II and citrate synthase (both ~30%) and for complex IV (90%), in only the RET group. We demonstrate that this type of progressive resistance training offers various improvements (e.g., strength, power, aerobic capacity, glucose tolerance, and plasma lipid profile).

Absence of leucine in an essential amino acid supplement reduces activation of mTORC1 signalling following resistance exercise in young females.

The purpose of the study was to investigate the specific effect of leucine on mTORC1 signalling and amino acid metabolism in connection with resistance exercise. Comparisons were made between ingestion of supplements with and without leucine. Eight young women performed leg press exercise on 2 occasions. In randomized order they received either an aqueous solution of essential amino acids with leucine (EAA) or without leucine (EAA-Leu), given as small boluses throughout the experiment. Muscle biopsies were taken after an overnight fast before exercise and 1 and 3 h postexercise and samples of blood were taken repeatedly during the experiment. Plasma and muscle concentrations of leucine rose 60%-140% (p < 0.05) with EAA and fell 35%-45% (p < 0.05) with the EAA-Leu supplement. In the EAA-trial, plasma and muscle levels of tyrosine (not present in the supplement) and the sum of the EAA were 15%-25% (p < 0.05) lower during recovery. Phosphorylation of mTOR and p70S6k was elevated to a larger extent following 1 h of recovery with leucine in the supplement (120% vs. 49% (p < 0.05) and 59- vs. 8-fold (p < 0.05) for EAA and EAA-Leu, respectively). The levels of MAFbx and MuRF-1 mRNA and of the corresponding proteins were not significantly altered after 3 h recovery from exercise. In conclusion, the presence of leucine in the supplement enhances the stimulatory effect on mTORC1 signalling and reduces the level of tyrosine and the sum of the EAA in muscle and plasma, suggesting a stimulation of protein synthesis and (or) inhibition of breakdown, leading to improvement in net protein balance.

Resistance exercise induced mTORC1 signaling is not impaired by subsequent endurance exercise in human skeletal muscle.

The current dogma is that the muscle adaptation to resistance exercise is blunted when combined with endurance exercise. The suggested mechanism (based on rodent experiments) is that activation of adenosine monophosphate-activated protein kinase (AMPK) during endurance exercise impairs muscle growth through inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). The purpose of this study was to investigate potential interference of endurance training on the signaling pathway of resistance training [mTORC1 phosphorylation of ribosomal protein S6 kinase 1 (S6K1)] in human muscle. Ten healthy and moderately trained male subjects performed on two separate occasions either acute high-intensity and high-volume resistance exercise (leg press, R) or R followed by 30 min of cycling (RE). Muscle biopsies were collected before and 1 and 3 h post resistance exercise. Phosphorylation of mTOR (Ser²448) increased 2-fold (P < 0.05) and that of S6K1 (Thr³89) 14-fold (P < 0.05), with no difference between R and RE. Phosphorylation of eukaryotic elongation factor 2 (eEF2, Thr56) was reduced ~70% during recovery in both trials (P < 0.05). An interesting finding was that phosphorylation of AMPK (Thr¹7²) and acetyl-CoA carboxylase (ACC, Ser79) decreased ~30% and ~50%, respectively, 3 h postexercise (P < 0.05). Proliferator-activated receptor-γ coactivator-1 (PGC-1α) mRNA increased more after RE (6.5-fold) than after R (4-fold) (RE vs. R: P < 0.01) and was the only gene expressed differently between trials. These data show that the signaling of muscle growth through the mTORC1-S6K1 axis after heavy resistance exercise is not inhibited by subsequent endurance exercise. It is also suggested that prior activation of mTORC1 signaling may repress subsequent phosphorylation of AMPK.