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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.

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.

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.

Broos S.,Exercise Physiology Research Group | Malisoux L.,Luxembourg Institute of Health | Theisen D.,Luxembourg Institute of Health | Van Thienen R.,Exercise Physiology Research Group | And 6 more authors.
PLoS ONE | Year: 2016

Purpose To examine the effect of α-actinin-3 deficiency due to homozygosity for the ACTN3 577Xallele on contractile and morphological properties of fast muscle fibers in non-athletic young men. Methods A biopsy was taken from the vastus lateralis of 4 RR and 4 XX individuals to test for differences in morphologic and contractile properties of single muscle fibers. The cross-sectional area of the fiber and muscle fiber composition was determined using standard immunohistochemistry analyses. Skinned single muscle fibers were subjected to active tests to determine peak normalized force (P0 ), maximal unloading velocity (V0 ) and peak power. A passive stretch test was performed to calculate Young's Modulus and hysteresis to assess fiber visco-elasticity. Results No differences were found in muscle fiber composition. The cross-sectional area of type IIa and IIx fibers was larger in RR compared to XX individuals (P<0.001). P0 was similar in both groups over all fiber types. A higher V0 was observed in type IIa fibers of RR genotypes (P<0.001) but not in type I fibers. The visco-elasticity as determined by Young's Modulus and hysteresis was unaffected by fiber type or genotype. Conclusion The greater V0 and the larger fast fiber CSA in RR compared to XX genotypes likely contribute to enhanced whole muscle performance during high velocity contractions. © 2016 Broos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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