Andreas Buch Møller

Muscle morphological and strength adaptations to endurance vs. resistance training

Farup, J, Kjølhede, T, Sørensen, H, Dalgas, U, Møller, AB, Vestergaard, PF, Ringgaard, S, Bojsen-Møller, J, and Vissing, K. Muscle morphological and strength adaptations to endurance vs. resistance training. J Strength Cond Res 26(2): 398–407, 2012—Fascicle angle (FA) is suggested to increase as a result of fiber hypertrophy and furthermore to serve as the explanatory link in the discrepancy in the relative adaptations in the anatomical cross-sectional area (CSA) and fiber CSA after resistance training (RT). In contrast to RT, the effects of endurance training on FA are unclear. The purpose of this study was therefore to investigate and compare the longitudinal effects of either progressive endurance training (END, n = 7) or RT (n = 7) in young untrained men on FA, anatomical CSA, and fiber CSA. Muscle morphological measures included the assessment of vastus lateralis FA obtained by ultrasonography and anatomical CSA by magnetic resonance imaging of the thigh and fiber CSA deduced from histochemical analyses of biopsy samples from m. vastus lateralis. Functional performance measures included &OV0312;;O2max and maximal voluntary contraction (MVC). The RT produced increases in FA by 23 ± 8% (p < 0.01), anatomical CSA of the knee extensor muscles by 9 ± 3% (p = 0.001), and fiber CSA by 19 ± 7% (p < 0.05). RT increased knee extensor MVC by 20 ± 5% (p < 0.001). END increased &OV0312;;O2max by 10 ± 2% but did not evoke changes in FA, anatomical CSA, or in fiber CSA. In conclusion, the morphological changes induced by 10 weeks of RT support that FA does indeed serve as the explanatory link in the observed discrepancy between the changes in anatomical and fiber CSA. Contrarily, 10 weeks of endurance training did not induce changes in FA, but the lack of morphological changes from END indirectly support the fact that fiber hypertrophy and FA are interrelated.

Physical exercise increases autophagic signaling through ULK1 in human skeletal muscle

Data from transgenic animal models suggest that exercise-induced autophagy is critical for adaptation to physical training, and that Unc-51 like kinase-1 (ULK1) serves as an important regulator of autophagy. Phosphorylation of ULK1 at Ser(555) stimulates autophagy, whereas phosphorylation at Ser(757) is inhibitory. To determine whether exercise regulates ULK1 phosphorylation in humans in vivo in a nutrient-dependent manner, we examined skeletal muscle biopsies from healthy humans after 1-h cycling exercise at 50% maximal O2 uptake on two occasions: 1) during a 36-h fast, and 2) during continuous glucose infusion at 0.2 kg/h. Physical exercise increased ULK1 phosphorylation at Ser(555) and decreased lipidation of light chain 3B. ULK1 phosphorylation at Ser(555) correlated positively with AMP-activated protein kinase-α Thr(172) phosphorylation and negatively with light chain 3B lipidation. ULK1 phosphorylation at Ser(757) was not affected by exercise. Fasting increased ULK1 and p62 protein expression, but did not affect exercise-induced ULK1 phosphorylation. These data demonstrate that autophagy signaling is activated in human skeletal muscle after 60 min of exercise, independently of nutritional status, and suggest that initiation of autophagy constitutes an important physiological response to exercise in humans.

Validity and variability of the 5-repetition sit-to-stand test in patients with multiple sclerosis

Purpose: To investigate; (i) the relationship between the 5STS-test and lower extremity muscle strength and balance, and (ii) the variability of the 5STS-test in multiple sclerosis (MS) patients. Method: 22 MS patients were divided into two groups (Group A and Group B) who completed one 5STS familiarization test session and two testing sessions. In Group A, session 1 also included assessment of lower extremity muscle strength. Session 2 and 3 involved completion of two 5STS-tests and assessment of balance. In Group B, session 2 and 3 involved completion of two rounds of two 5STS-tests separated by a 30 min break. Results: Significant correlations were found between the 5STS-test and isometric and isokinetic knee flexor and extensor muscle strength of the most affected leg (R = −0.60 to −0.77), and between the 5STS-test and balance performance (R = 0.69). Intra-assessor day-to-day variability, intra-assessor test-retest variability and intra-assessor variability within test were 25.5, 22.3, and 23.1%, respectively. Inter-assessor variability within test and inter-assessor variability were 23.4 and 5.9%, respectively. Conclusions: The 5STS-test is related to lower extremity muscle strength and to balance performance in MS patients. For interventional purposes, a change of >25% can be regarded as a real change. Implications for Rehabilitation The 5STS-test is a valid measure of lower extremity muscle strength of the most affected leg in patients with MS. For interventional purposes, a change of more than 25% can be regarded as a real change. Familiarization to the 5STS-test has to be performed to achieve reliable results.

Direct effects of TNF-α on local fuel metabolism and cytokine levels in the placebo controlled bilaterally infused human leg; increased insulin sensitivity, increased net protein breakdown and increased IL-6 release.

Tumor necrosis factor-α (TNF-α) has widespread metabolic actions. Systemic TNF-α administration, however, generates a complex hormonal and metabolic response. Our study was designed to test whether regional, placebo-controlled TNF-α infusion directly affects insulin resistance and protein breakdown. We studied eight healthy volunteers once with bilateral femoral vein and artery catheters during a 3-h basal period and a 3-h hyperinsulinemic-euglycemic clamp. One artery was perfused with saline and one with TNF-α. During the clamp, TNF-α perfusion increased glucose arteriovenous differences (0.91 ± 0.17 vs. 0.74 ± 0.15 mmol/L, P = 0.012) and leg glucose uptake rates. Net phenylalanine release was increased by TNF-α perfusion with concomitant increases in appearance and disappearance rates. Free fatty acid kinetics was not affected by TNF-α, whereas interleukin-6 (IL-6) release increased. Insulin and protein signaling in muscle biopsies was not affected by TNF-α. TNF-α directly increased net muscle protein loss, which may contribute to cachexia and general protein loss during severe illness. The finding of increased insulin sensitivity, which could relate to IL-6, is of major clinical interest and may concurrently act to provide adequate tissue fuel supply and contribute to the occurrence of systemic hypoglycemia. This distinct metabolic feature places TNF-α among the rare insulin mimetics of human origin.

Fasting increases human skeletal muscle net phenylalanine release and this is associated with decreased mTOR signaling

Aim Fasting is characterised by profound changes in energy metabolism including progressive loss of body proteins. The underlying mechanisms are however unknown and we therefore determined the effects of a 72-hour-fast on human skeletal muscle protein metabolism and activation of mammalian target of rapamycin (mTOR), a key regulator of cell growth. Methods Eight healthy male volunteers were studied twice: in the postabsorptive state and following 72 hours of fasting. Regional muscle amino acid kinetics was measured in the forearm using amino acid tracers. Signaling to protein synthesis and breakdown were assessed in skeletal muscle biopsies obtained during non-insulin and insulin stimulated conditions on both examination days. Results Fasting significantly increased forearm net phenylalanine release and tended to decrease phenylalanine rate of disappearance. mTOR phosphorylation was decreased by ∼50% following fasting, together with reduced downstream phosphorylation of 4EBP1, ULK1 and rpS6. In addition, the insulin stimulated increase in mTOR and rpS6 phosphorylation was significantly reduced after fasting indicating insulin resistance in this part of the signaling pathway. Autophagy initiation is in part regulated by mTOR through ULK1 and fasting increased expression of the autophagic marker LC3B-II by ∼30%. p62 is degraded during autophagy but was increased by ∼10% during fasting making interpretation of autophagic flux problematic. MAFbx and MURF1 ubiquitin ligases remained unaltered after fasting indicating no change in protesomal protein degradation. Conclusions Our results show that during fasting increased net phenylalanine release in skeletal muscle is associated to reduced mTOR activation and concomitant decreased downstream signaling to cell growth.

Validity and reliability of VO2-max measurements in persons with multiple sclerosis

BACKGROUND Direct measurement of whole body maximal oxygen consumption (VO2-max test) is considered the gold standard when assessing cardiorespiratory fitness. Nonetheless, the validity and reliability of the test have not been examined in persons with multiple sclerosis (PwMS). OBJECTIVE To investigate the validity and reliability of VO2-max measurements in PwMS, and additionally to compare these measures to those of healthy controls. METHODS Twenty PwMS completed two incremental VO2-max tests on a leg cycling ergometer. Test validity was analyzed based on the first VO2-max test in the total sample and in patient subgroups based on Expanded Disability Status Scale (EDSS) scores (EDSS≤2.5, n=10 and EDSS≥3.0, n=10) by evaluation of the primary VO2 plateau criterion and four common secondary validity criteria. Data from 20 age- and gender-matched healthy controls were used for comparison. The second VO2-max test was used to establish day-to-day reliability. RESULTS In PwMS 40% were able to achieve the primary validity criterion for VO2-max measurements, while 65-95% were able to achieve the secondary criteria. This corresponded to the age-matched healthy controls. Strong correlations were found between measurements of VO2-max and between the validity criteria from test 1 compared to test 2 in PwMS. MS disability level did not influence criteria attainment. The variability analysis exhibited a 95% prediction interval of -238 to 201 mL·min(-1) (-9.8 to 8.1%) for the difference between the two measurements of VO2-max. CONCLUSION In mild to moderately impaired PwMS less than half achieve the primary validity criterion when performing a VO2-max test, but the high reliability and the better achievement of the secondary criteria implies that a valid test of VO2-max can be performed, at a level corresponding to that of healthy controls. The day-to-day variation implies that a change of more than 10% in VO2-max is required to be interpreted as a real change.

Heat sensitive persons with multiple sclerosis are more tolerant to resistance exercise than to endurance exercise

Background: Heat sensitivity (HS) is reported by 58% of all persons with multiple sclerosis (MS), causing symptom exacerbation possibly limiting exercise participation. Objective: The purpose of this study was to test the hypotheses that (a) a relationship between exercise-induced changes in core–temperature (Ctemp) and changes in symptom intensity exists, and (b) that resistance exercise (RE), as a consequence of a minor increase in core temperature, will induce a lesser worsening of symptoms than endurance exercise (EE) in HS persons with MS. Methods: On two separate days, 16 HS persons with MS randomly completed a session of RE and EE, or EE and RE, respectively. Testing was conducted pre, post and one hour after exercise and consisted of Visual Analogue Scale (VAS) scoring (fatigue, spasticity, pain, strength, walking and balance), the 5-time sit-to-stand (5STS), the Multiple Sclerosis Functional Composite (MSFC) and Body Sway. Composite scores describing average subjective symptom intensity (SI) and total number of symptoms (SN) were calculated from VAS scores. Results: Ctemp (0.9±0.4°C vs 0.3±0.1°C, p<0.001), SI (1.7±1.9 cm vs 0.6±1.5 cm, p<0.05) and SN (1.6±1.9 vs 0.6±2.1, p<0.05) increased significantly more during EE than RE. Changes in Ctemp correlated to changes in SI (r=0.50, p<0.01). No differences were observed in 5STS, MSFC and Body Sway scores after EE when compared to RE. Conclusion: An exercise-induced increase in Ctemp is associated with increased number and severity of perceived symptoms in HS persons with MS. Based on these findings it is expected that HS persons with MS do tolerate RE better than EE.

AMP kinase in exercise adaptation of skeletal muscle.

Regular physical exercise has undisputed health benefits in the prevention and the treatment of many diseases. Understanding the mechanisms that regulate adaptations to exercise training therefore has obvious clinical perspectives. Several lines of evidence suggest that the AMP-activated protein kinase (AMPK) has a central role as a master metabolic regulator in skeletal muscle. Exercise is a potent activator of AMPK, and AMPK signaling can play a key part in regulating protein turnover during and after exercise training.

Resistance exercise, but not endurance exercise, induces IKKβ phosphorylation in human skeletal muscle of training-accustomed individuals

The mammalian target of rapamycin complex 1 (mTORC1) is considered an important role in the muscular adaptations to exercise. It has been proposed that exercise-induced signaling to mTORC1 do not require classic growth factor PI3K/Akt signaling. Activation of IKKβ and the mitogen-activated protein kinases (MAPKs) Erk1/2 and p38 has been suggested to link inflammation and cellular stress to activation of mTORC1 through the tuberous sclerosis 1 (TSC1)/tuberous sclerosis 2 (TSC2) complex. Consequently, activation of these proteins constitutes potential alternative mechanisms of mTORC1 activation following exercise. Previously, we demonstrated that mTOR is preferentially activated in response to resistance exercise compared to endurance exercise in trained individuals without concomitant activation of Akt. In the present study, we extended this investigation by examining IκB kinase complex (IKK), TSC1, MAPK, and upstream Akt activators, along with gene expression of selected cytokines, in skeletal muscles from these subjects. Biopsies were sampled prior to, immediately after, and in the recovery period following resistance exercise, endurance exercise, and control interventions. The major finding was that IKKβ phosphorylation increased exclusively after resistance exercise. No changes in TSC1, Erk1/2, insulin receptor, or insulin receptor substrate 1 phosphorylation were observed in any of the groups, while p38 phosphorylation was higher in the resistance exercise group compared to both other groups immediately after the intervention. Resistance and endurance exercise increased IL6, IL8, and TNFα gene expression immediately after exercise. The non-exercise control group demonstrated that cytokine gene expression is also sensitive to repeated biopsy sampling, whereas no effect of repeated biopsy sampling on protein expression and phosphorylation was observed. In conclusion, resistance exercise, but not endurance exercise, increases IKKβ phosphorylation in trained human subjects, which support the idea that IKKβ can influence the activation of mTORC1 in human skeletal muscle.

Sustained AS160 and TBC1D1 phosphorylations in human skeletal muscle 30 min after a single bout of exercise

BACKGROUND phosphorylation of AS160 and TBC1D1 plays an important role for GLUT4 mobilization to the cell surface. The phosphorylation of AS160 and TBC1D1 in humans in response to acute exercise is not fully characterized. OBJECTIVE to study AS160 and TBC1D1 phosphorylation in human skeletal muscle after aerobic exercise followed by a hyperinsulinemic euglycemic clamp. DESIGN eight healthy men were studied on two occasions: 1) in the resting state and 2) in the hours after a 1-h bout of ergometer cycling. A hyperinsulinemic euglycemic clamp was initiated 240 min after exercise and in a time-matched nonexercised control condition. We obtained muscle biopsies 30 min after exercise and in a time-matched nonexercised control condition (t = 30) and after 30 min of insulin stimulation (t = 270) and investigated site-specific phosphorylation of AS160 and TBC1D1. RESULTS phosphorylation on AS160 and TBC1D1 was increased 30 min after the exercise bout, whereas phosphorylation of the putative upstream kinases, Akt and AMPK, was unchanged compared with resting control condition. Exercise augmented insulin-stimulated phosphorylation on AS160 at Ser(341) and Ser(704) 270 min after exercise. No additional exercise effects were observed on insulin-stimulated phosphorylation of Thr(642) and Ser(588) on AS160 or Ser(237) and Thr(596) on TBC1D1. CONCLUSIONS AS160 and TBC1D1 phosphorylations were evident 30 min after exercise without simultaneously increased Akt and AMPK phosphorylation. Unlike TBC1D1, insulin-stimulated site-specific AS160 phosphorylation is modified by prior exercise, but these sites do not include Thr(642) and Ser(588). Together, these data provide new insights into phosphorylation of key regulators of glucose transport in human skeletal muscle.