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Broos S.,Exercise Physiology Research Group | Malisoux L.,Sports Medicine Research Laboratory | Theisen D.,Sports Medicine Research Laboratory | Francaux M.,Catholic University of Louvain | And 2 more authors.
PLoS ONE | Year: 2012

A common nonsense polymorphism in the ACTN3 gene results in the absence of α-actinin-3 in XX individuals. The wild type allele has been associated with power athlete status and an increased force output in numeral studies, though the mechanisms by which these effects occur are unclear. Recent findings in the Actn3-/- (KO) mouse suggest a shift towards 'slow' metabolic and contractile characteristics of fast muscle fibers lacking α-actinin-3. Skinned single fibers from the quadriceps muscle of three men with spinal cord injury (SCI) were tested regarding peak force, unloaded shortening velocity, force-velocity relationship, passive tension and calcium sensitivity. The SCI condition induces an 'equal environment condition' what makes these subjects ideal to study the role of α-actinin-3 on fiber type expression and single muscle fiber contractile properties. Genotyping for ACTN3 revealed that the three subjects were XX, RX and RR carriers, respectively. The XX carrier's biopsy was the only one that presented type I fibers with a complete lack of type IIx fibers. Properties of hybrid type IIa/IIx fibers were compared between the three subjects. Absence of α-actinin-3 resulted in less stiff type IIa/IIx fibers. The heterozygote (RX) exhibited the highest fiber diameter (0.121±0.005 mm) and CSA (0.012±0.001 mm2) and, as a consequence, the highest peak force (2.11±0.14 mN). Normalized peak force was similar in all three subjects (P = 0.75). Unloaded shortening velocity was highest in R-allele carriers (P<0.001). No difference was found in calcium sensitivity. The preservation of type I fibers and the absence of type IIx fibers in the XX individual indicate a restricted transformation of the muscle fiber composition to type II fibers in response to long-term muscle disuse. Lack of α-actinin-3 may decrease unloaded shortening velocity and increase fiber elasticity. © 2012 Broos et al.


Pierre N.,Catholic University of Louvain | Deldicque L.,Exercise Physiology Research Group | Barbe C.,Catholic University of Louvain | Naslain D.,Catholic University of Louvain | And 2 more authors.
PLoS ONE | Year: 2013

The purpose of this study was to investigate whether toll-like receptor 4 (TLR4) is implicated in the development of endoplasmic reticulum stress (ER stress) observed after a high-fat diet (HFD) in liver, skeletal muscle and adipose tissue. TLR4-/- and C57BL/6J wild-type mice (WT) were fed with chow or HFD (45% calories from fat) during 18 weeks. An oral glucose tolerance-test was performed. The animals were sacrificed in a fasted state and the tissues were removed. TLR4 deletion protected from body weight gain and glucose intolerance induced by HFD whereas energy intake was higher in transgenic mice suggesting larger energy expenditure. HFD induced an ER stress in skeletal muscle, liver and adipose tissue of WT mice as assessed by BiP, CHOP, spliced and unspliced XBP1 and phospho-eIF2α. TLR4-/- mice were protected against HFD-induced ER stress. Then, we investigated the main signaling downstream of TLR4 namely the NF-κB pathway, expecting to identify the mechanism by which TLR4 is able to activate ER stress. The mRNA levels of cytokines regulated by NF-κB namely TNFα, IL-1β and IL-6, were not changed after HFD and phospho-IκB-α (ser 32) was not changed. Our results indicate that TLR4 is essential for the development of ER stress related to HFD. Nevertheless, the NFκ-B pathway does not seem to be directly implicated. The reduced fat storage in TLR4-/- mice could explain the absence of an ER stress after HFD. © 2013 Pierre et al.


Sylow L.,Copenhagen University | Moller L.L.V.,Copenhagen University | D'Hulst G.,Exercise Physiology Research Group | Schjerling P.,Copenhagen University | And 2 more authors.
Endocrinology | Year: 2016

Exercise has a potent insulin-sensitivity enhancing effect on skeletal muscle, but the intracellular mechanisms that mediate this effect are not well understood. In muscle, Ras-related C3 botulinum toxin substrate 1 (Rac1) regulates both insulin- and contraction-stimulated glucose transport and is dysregulated in insulin resistant muscle. However, whether Rac1 is involved in mediating enhanced insulin sensitivity after an acute bout of exercise is unresolved. To address this question, we investigated after exercise whole-body (insulin tolerance test) as well as muscle (insulin-stimulated 2-deoxyglucose transport in isolated soleus muscle) insulin sensitivity in inducible muscle-specific Rac1 knockout (mKO) and wild-type (WT) littermate mice. Previous exercise enhanced whole-body insulin sensitivity by 40% in WT mice and rescued the insulin intolerance in Rac1 mKO mice by improving whole-body insulin sensitivity by 230%. In agreement, previous exercise significantly improved insulin sensitivity by 20% in WT and by 40% in Rac1 mKO soleus muscles. These findings suggest that muscle Rac1 is dispensable for the insulin sensitizing effect of exercise. Moreover, insulin resistance in Rac1 mKO mice can be completely normalized by previous exercise explaining why insulin resistant patients can increase insulin action with exercise despite dysfunctional Rac1 activity in muscle © 2016 by the Endocrine Society.


D'Hulst G.,Exercise Physiology Research Group | Jamart C.,Catholic University of Louvain | Van Thienen R.,Exercise Physiology Research Group | Hespel P.,Exercise Physiology Research Group | And 2 more authors.
Acta Physiologica | Year: 2013

Hypoxia-induced muscle wasting has been observed in several environmental and pathological conditions. However, the molecular mechanisms behind this loss of muscle mass are far from being completely elucidated, certainly in vivo. When studying the regulation of muscle mass by environmental hypoxia, many confounding factors have to be taken into account, such as decreased protein ingestion, sleep deprivation or reduced physical activity, which make difficult to know whether hypoxia per se causes a reduction in muscle mass. Aim: We hypothesized that acute exposure to normobaric hypoxia (11% O2) would repress the activation of the mTOR pathway usually observed after a meal and would activate the proteolytic pathways in skeletal muscle. Methods: Fifteen subjects were exposed passively for 4 h to normoxic and hypoxic conditions in a random order after consumption of a light breakfast. A muscle biopsy and a blood sample were taken before, after 1 and 4 h of exposure. Results: After 4 h, plasma insulin concentration and the phosphorylation state of PKB and S6K1 in skeletal muscle were higher in hypoxia than in normoxia (P < 0.05). At the same time, Redd1 mRNA level was upregulated (P < 0.05), whilst MAFbx mRNA decreased (P < 0.05) in hypoxia compared with normoxia. Proteasome, cathepsin L and calpain activities were not altered by environmental hypoxia. Conclusion: Contrary to our hypothesis and despite an increase in the mRNA level of Redd1, an inhibitor of the mTORC1 pathway, short-term acute environmental hypoxia induced a higher response of PKB and S6K1 to a meal, which may be due to increased plasma insulin concentration. © 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.


Puype J.,Exercise Physiology Research Group | Ramaekers M.,Exercise Physiology Research Group | Van Thienen R.,Exercise Physiology Research Group | Deldicque L.,Exercise Physiology Research Group | Hespel P.,Exercise Physiology Research Group
Scandinavian Journal of Medicine and Science in Sports | Year: 2015

We investigated whether dietary nitrate (NO3 -) supplementation enhances the effect of training in hypoxia on endurance performance at sea level. Twenty-two healthy male volunteers performed high-intensity endurance training on a cycle ergometer (6 weeks, 5×30min/week at 4-6mmol/L blood lactate) in normobaric hypoxia (12.5% FiO2), while ingesting either beetroot juice [0.07mmol NO3 -/kg body weight (bw)/day; BR, n=11] or a control drink (CON, n=11). During the pretest and the posttest, the subjects performed a 30-min simulated time trial (TT) and an incremental VO2max test. Furthermore, a biopsy was taken from m. vastus lateralis before and after the TT. Power output during the training sessions in both groups increased by ∼6% from week 1 to week 6 (P<0.05). Compared with the pretest, VO2max in the posttest was increased (P<0.05) in CON (5%) and BR (9%). Power output corresponding with the 4mmol/L blood lactate threshold, as well as mean power output during TT increased by ∼16% in both groups (P<0.05). Muscle phospho-AMP-activated protein kinase, hypoxia inducible factor-1α mRNA content, and glycogen breakdown during the TT were similar between the groups in both the pretest and the posttest. In conclusion, low-dose dietary NO3 - supplementation does not enhance the effects of intermittent hypoxic training on endurance exercise performance at sea level. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Pierre N.,Catholic University of Louvain | Barbe C.,Catholic University of Louvain | Gilson H.,Catholic University of Louvain | Deldicque L.,Exercise Physiology Research Group | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2014

The purpose of this study was to examine the link between oxidative stress and endoplasmic reticulum (ER) stress in myogenic cells. C2C12 myotubes were incubated with hydrogen peroxide (H2O2, 200 μM) and harvested 4 h or 17 h after the induction of this oxidative stress. A massive upregulation of binding immunoglobulin protein (BiP) was found, indicating the presence of ER stress. Nevertheless, the three branches of the unfolded protein response (UPR) were not activated to the same extent. The double-stranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK) branch was the most activated as shown by the increase of phospho-eukaryotic translation-initiation factor 2α (eIF2α, Ser51) and the mRNA levels of activating transcription factor 4 (ATF4), C/EBP homologous (CHOP) and tribbles homolog 3 (TRB3). The slight increase in the spliced form of X-box binding protein 1 (XBP1s) together with the decrease of the unspliced form (XBP1u) indicated a higher endoribonuclease activity of inositol-requiring 1α (IRE1α). The transcriptional activity of activating transcription factor 6 (ATF6) remained unchanged after incubation with H2O2. The mechanisms by which the three branches of UPR can be specifically regulated by oxidative stress are currently unresolved and need further investigations. © 2014 Elsevier Inc. All rights reserved.


Deldicque L.,Exercise Physiology Research Group
Frontiers in Physiology | Year: 2013

Skeletal muscle is vital to life as it provides the mechanical power for locomotion, posture and breathing. Beyond these vital functions, skeletal muscle also plays an essential role in the regulation of whole body metabolism, e.g., glucose homeostasis. Although progressive loss of muscle mass with age seems unavoidable, it is critical for older people to keep the highest mass as possible. It is clear that the origin of sarcopenia is multifactorial but, in the present review, it was deliberately chosen to evaluate the likely contribution of one specific cellular stress, namely the endoplasmic reticulum (ER) stress. It is proposed that ER stress can: (1) directly impact muscle mass as one fate of prolonged and unresolved ER stress is cell death and; (2) indirectly create a state of anabolic resistance by inhibiting the mammalian target of rapamycin complex 1 (mTORC1) pathway. With age, many of the key components of the unfolded protein response, such as the chaperones and enzymes, display reduced expression and activity resulting in a dysfunctional ER, accelerating the rate of proteins discarded via the ER-associated degradation. In addition, ER stress can block the mTORC1 pathway which is essential in the response to the anabolic stimulus of nutrients and contractile activity thereby participating to the well-known anabolic resistance state in skeletal muscle during ageing. As exercise increases the expression of several chaperones, it could anticipate or restore the loss of unfolded protein response components with age and thereby reduce the level of ER stress. This hypothesis has not been tested yet but it could be a new mechanism behind the beneficial effects of exercise in the elderly not only for the preservation of muscle mass but also for the regulation of whole body metabolism. © 2013 Deldicque.


Ballak S.B.,Manchester Metropolitan University | Ballak S.B.,VU University Amsterdam | Jaspers R.T.,VU University Amsterdam | Deldicque L.,Exercise Physiology Research Group | And 6 more authors.
Experimental Gerontology | Year: 2015

Background: Sarcopenia contributes to the decreased quality of life in the older person. While resistance exercise is an effective measure to increase muscle mass and strength, the hypertrophic response may be blunted in old age. Objectives: To determine 1) whether hypertrophy in the m. plantaris of old mice was blunted compared to adult and 2) whether this was related to a reduced satellite cell (SC) density and 3) how resveratrol affects hypertrophy in old mice. Methods: In adult (7.5. months, n. = 11), old (23.5. months, n. = 10) and old-resveratrol-treated (n. = 10) male C57BL/6J mice, hypertrophy of the left m. plantaris was induced by denervation of its synergists. The contralateral leg served as control. Results: After six weeks, overload-induced myofiber hypertrophy and IIB-IIA shift in myofiber type composition were less pronounced in old than adult mice (P. = 0.03), irrespective of resveratrol treatment. Muscles from old mice had a lower SC density than adult muscles (P. = 0.002). Overload-induced SC proliferation (P. <. 0.05) resulted in an increased SC density in old, but not adult muscles (P. = 0.02), while a decrease occurred after resveratrol supplementation (P. = 0.044). Id2 and myogenin protein expression levels were higher in old than adult muscles (P. <. 0.05). Caspase-3 was expressed more in hypertrophied than control muscles and was reduced with resveratrol (P. <. 0.05). Conclusion: The blunted hypertrophic response in old mice was associated with a lower SC density, but there was no evidence for a lower capacity for proliferation. Resveratrol did not rescue the hypertrophic response and even reduced, rather than increased, the number of SCs in hypertrophied muscles. © 2014 Elsevier Inc.


PubMed | VU University Amsterdam, Exercise Physiology Research Group and Manchester Metropolitan University
Type: Journal Article | Journal: Age (Dordrecht, Netherlands) | Year: 2016

We hypothesize that the attenuated hypertrophic response in old mouse muscle is (1) partly due to a reduced capillarization and angiogenesis, which is (2) accompanied by a reduced oxidative capacity and fatigue resistance in old control and overloaded muscles, that (3) can be rescued by the antioxidant resveratrol. To investigate this, the hypertrophic response, capillarization, oxidative capacity, and fatigue resistance of m. plantaris were compared in 9- and 25-month-old non-treated and 25-month-old resveratrol-treated mice. Overload increased the local capillary-to-fiber ratio less in old (15%) than in adult (59%) muscle (P<0.05). Although muscles of old mice had a higher succinate dehydrogenase (SDH) activity (P<0.05) and a slower fiber type profile (P<0.05), the isometric fatigue resistance was similar in 9- and 25-month-old mice. In both age groups, the fatigue resistance was increased to the same extent after overload (P<0.01), without a significant change in SDH activity, but an increased capillary density (P<0.05). Attenuated angiogenesis during overload may contribute to the attenuated hypertrophic response in old age. Neither was rescued by resveratrol supplementation. Changes in fatigue resistance with overload and aging were dissociated from changes in SDH activity, but paralleled those in capillarization. This suggests that capillarization plays a more important role in fatigue resistance than oxidative capacity.


PubMed | Catholic University of Louvain, Exercise Physiology Research Group, University of Milan Bicocca and Victoria University of Melbourne
Type: | Journal: Hypoxia (Auckland, N.Z.) | Year: 2016

Chronic hypoxia leads to muscle atrophy. The molecular mechanisms responsible for this phenomenon are not well defined in vivo. We sought to determine how chronic hypoxia regulates molecular markers of protein synthesis and degradation in human skeletal muscle and whether these regulations were related to the regulation of the hypoxia-inducible factor (HIF) pathway. Eight young male subjects lived in a normobaric hypoxic hotel (FiO

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