Sébastien Dufresne - Academia.edu (original) (raw)

Papers by Sébastien Dufresne

BMC Musculoskeletal Disorders, Oct 28, 2016

Background: Cumulative evidence indicates that statins induce myotoxicity. However, the lack of u... more Background: Cumulative evidence indicates that statins induce myotoxicity. However, the lack of understanding of how statins affect skeletal muscles at the structural, functional, and physiological levels hampers proper healthcare management. The purpose of the present study was to investigate the early after-effects of lovastatin on the slowtwitch soleus (Sol) and fast-twitch extensor digitorum longus (EDL) muscles. Methods: Adult C57BL/6 mice were orally administrated with placebo or lovastatin [50 mg/kg/d] for 28 days. At the end of the treatment, the isometric ex vivo contractile properties of the Sol and EDL muscles were measured. Subtetanic and tetanic contractions were assessed and contraction kinetics were recorded. The muscles were then frozen for immunohistochemical analyses. Data were analyzed by two-way ANOVA followed by an a posteriori Tukey's test. Results: The short-term lovastatin treatment did not induce muscle mass loss, muscle fiber atrophy, or creatine kinase (CK) release. It had no functional impact on slow-twitch Sol muscles. However, subtetanic stimulations at 10 Hz provoked greater force production in fast-twitch EDL muscles. The treatment also decreased the maximal rate of force development (dP/dT) of twitch contractions and prolonged the half relaxation time (1/2RT) of tetanic contractions of EDL muscles. Conclusions: An early short-term statin treatment induced subtle but significant changes in some parameters of the contractile profile of EDL muscles, providing new insights into the selective initiation of statin-induced myopathy in fasttwitch muscles.

American Journal of Pathology, Mar 1, 2017

American Journal of Physiology-cell Physiology, Apr 15, 2016

of nuclear factor-B (RANK), its ligand RANKL, and the soluble decoy receptor osteoprotegerin are ... more of nuclear factor-B (RANK), its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Here we show that RANK is also expressed in fully differentiated myotubes and skeletal muscle. Muscle RANK deletion has inotropic effects in denervated, but not in sham, extensor digitorum longus (EDL) muscles preventing the loss of maximum specific force while promoting muscle atrophy, fatigability, and increased proportion of fast-twitch fibers. In denervated EDL muscles, RANK deletion markedly increased stromal interaction molecule 1 content, a Ca 2ϩ sensor, and altered activity of the sarco(endo)plasmic reticulum Ca 2ϩ-ATPase (SERCA) modulating Ca 2ϩ storage. Muscle RANK deletion had no significant effects on the sham or denervated slowtwitch soleus muscles. These data identify a novel role for RANK as a key regulator of Ca 2ϩ storage and SERCA activity, ultimately affecting denervated skeletal muscle function. receptor-activator of nuclear factor-B; sarco(endo)plasmic reticulum Ca 2ϩ-ATPase RECEPTOR-ACTIVATOR OF NUCLEAR factor-B ligand (RANKL), the membrane receptor RANK, and the soluble decoy receptor osteoprotegerin (OPG) are members of the tumor necrosis factor superfamily that regulate bone remodeling (26, 29). RANK/RANKL interaction activates Ca 2ϩ-dependent and NF-B signaling pathways, which affect osteoclast differentiation, activation, and survival (29). The third protagonist, OPG, binds to RANKL and inhibits the RANK/RANKL interaction and subsequent osteoclastogenesis (46, 55). In addition to bone, RANK/RANKL has been detected in other tissues such as thymus, heart, kidney, liver, brain, blood vessels, and skeletal muscles (17, 32, 51). The RANK/RANKL pathway is

PLOS ONE, Sep 16, 2015

Objective To evaluate whether a 12-week supervised exercise program promotes an active lifestyle ... more Objective To evaluate whether a 12-week supervised exercise program promotes an active lifestyle throughout pregnancy in pregnant women with obesity. Methods In this preliminary randomised trial, pregnant women (body mass index ! 30 kg/m 2) were allocated to either standard care or supervised training, from 15 to 27 weeks of gestation. Physical activity was measured by accelerometry at 14, 28 and 36 weeks, while fitness (oxygen consumption (VO 2) at the anaerobic threshold), nutrition (caloric intake and macronutrients percentage) and anthropometry were assessed at 14 and 28 weeks of gestation. Analyses were performed using repeated measures ANOVA.

Receptors and clinical investigation, Apr 1, 2016

The bone remodeling and homeostasis are mainly controlled by the receptor-activator of nuclear fa... more The bone remodeling and homeostasis are mainly controlled by the receptor-activator of nuclear factor κB (RANK), its ligand RANKL, and the soluble decoy receptor osteoprotegerin (OPG) pathway. While there is a strong association between osteoporosis and skeletal muscle dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology remains elusive. Our recent article published in the American Journal of Physiology (Cell Physiology) showed that RANK is also expressed in fully differentiated C2C12 myotubes and skeletal muscles. We used the Cre-Lox approach to inactivate muscle RANK (RANK mko) and showed that RANK deletion preserves the force of denervated fast-twitch EDL muscles. However, RANK deletion had no positive impact on slow-twitch Sol muscles. In addition, denervating RANK mko EDL muscles induced an increase in the total calcium concentration ([CaT]), which was associated with a surprising decrease in SERCA activity. Interestingly, the levels of STIM-1, which mediates Ca 2+ influx following the depletion of SR Ca 2+ stores, were markedly higher in denervated RANK mko EDL muscles. We speculated that extracellular Ca 2+ influx mediated by STIM-1 may be important for the increase in [CaT] and the gain of force in denervated RANK mko EDL muscles. Overall, these findings showed for the first time that the RANKL/RANK interaction plays a role in denervation-induced muscle atrophy and dysfunction.

Acta neuropathologica communications, Apr 24, 2018

Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfuncti... more Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that regulates synchronously bone and skeletal muscle physiopathology is still elusive. Receptor-activator of nuclear factor κB (RANK), its ligand RANKL and the soluble decoy receptor osteoprotegerin (OPG) are the key regulators of osteoclast differentiation and bone remodelling. We thus hypothesized that RANK/RANKL/OPG, which is a key pathway for bone regulation, is involved in Duchenne muscular dystrophy (DMD) physiopathology. Our results show that muscle-specific RANK deletion (mdx-RANK mko) in dystrophin deficient mdx mice improves significantly specific force [54% gain in force] of EDL muscles with no protective effect against eccentric contraction-induced muscle dysfunction. In contrast, full-length OPG-Fc injections restore the force of dystrophic EDL muscles [162% gain in force], protect against eccentric contraction-induced muscle dysfunction ex vivo and significantly improve functional performance on downhill treadmill and post-exercise physical activity. Since OPG serves a soluble receptor for RANKL and as a decoy receptor for TRAIL, mdx mice were injected with anti-RANKL and anti-TRAIL antibodies to decipher the dual function of OPG. Injections of anti-RANKL and/or anti-TRAIL increase significantly the force of dystrophic EDL muscle [45% and 17% gains in force, respectively]. In agreement, truncated OPG-Fc that contains only RANKL domains produces similar gains, in terms of force production, than anti-RANKL treatments. To corroborate that full-length OPG-Fc also acts independently of RANK/RANKL pathway, dystrophin/RANK double-deficient mice were treated with full-length OPG-Fc for 10 days. Dystrophic EDL muscles exhibited a significant gain in force relative to untreated dystrophin/RANK double-deficient mice, indicating that the effect of full-length OPG-Fc is in part independent of the RANKL/RANK interaction. The sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) activity is significantly depressed in dysfunctional and dystrophic muscles and full-length OPG-Fc treatment increased SERCA activity and SERCA-2a expression. These findings demonstrate the superiority of full-length OPG-Fc treatment relative to truncated OPG-Fc, anti-RANKL, anti-TRAIL or muscle RANK deletion in improving dystrophic muscle function,

The FASEB Journal, Apr 1, 2014

Receptor-activator of nuclear factor-κB (RANK), its ligand RANKL and the soluble decoy receptor o... more Receptor-activator of nuclear factor-κB (RANK), its ligand RANKL and the soluble decoy receptor osteoprotegerin (OPG) are members of the tumor necrosis factor (TNF) superfamily that control osteoclast differentiation, bone remodelling and osteoporosis. Since bone and skeletal muscle physiopathology occurs synchronously, we tested whether RANK/RANKL pathway is involved in muscle dysfunction following different muscle wasting conditions. Contractile properties of EDL muscles were obtained following 14d of denervation in mice specifically deficient in RANK skeletal muscle or in dystrophic mdx mice treated daily for 10d with OPG [0.3mg/kg], the natural inhibitor of RANKL. The activity and expression of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) were determined in denervated or dystrophic muscles. RANK muscle deletion did not prevent atrophy but greatly reduced the losses of force production and SERCA activity in denervated EDL muscles. Force production of EDL muscles also increased by 140% in OPG-treated...

Neuromuscular Disorders, Oct 1, 2016

molecular methods, we evaluated and compared the benefits of second generation utrophin modulator... more molecular methods, we evaluated and compared the benefits of second generation utrophin modulators in the mdx diaphragm. The results of these evaluations will be presented and their relevance to their potential clinical development discussed.

The muscle membrane, sarcolemma, must be firmly attached to the basal lamina. The failure of prop... more The muscle membrane, sarcolemma, must be firmly attached to the basal lamina. The failure of proper attachment results in muscle injury, which is the underlying cause of Duchenne muscular dystrophy (DMD), where mutations in the dystrophin gene disrupts the firm adhesion. In DMD patients, even moderate contraction causes damage, leading to progressive muscle degeneration. The damaged muscles are repaired through myogenesis. Consequently, myogenesis is highly active in DMD patients, and the repeated activation of myogenesis leads to the exhaustion of the myogenic stem cells. Therefore, approaches to reducing the risk of the exhaustion are to develop a treatment that strengthens the interaction between the sarcolemma and the basal lamina, and increases the efficiency of myogenesis. Galectin-3 is an oligosaccharide-binding protein and known to be involved in cell-cell interactions and cell-matrix interactions. Galectin-3 is expressed in myoblasts and skeletal muscle while its function in muscle remains elusive. In this study, we found evidence that galectin-3 and the monosaccharide N-acetylglucosamine, which increases the ligands (oligosaccharides) of galectin-3, promotes myogenesis in vitro. Moreover, in the mdx mouse model of DMD, treatment with Nacetylglucosamine increased the muscle force production. Our results demonstrate that treatment with Nacetylglucosamine can mitigate the burden of DMD.

Journal of the American College of Cardiology

Background and AimsStatin-associated muscle symptoms (SAMS) are frequently reported. Nevertheless... more Background and AimsStatin-associated muscle symptoms (SAMS) are frequently reported. Nevertheless, few data on objective measures of muscle function are available. Recent data suggesting an important nocebo effect with statin use could confound such effects. The objective was to assess if subjective and objective measures of muscle function improve after drug withdrawal in SAMS reporters.MethodsPatients (59 men, 33 women, 50.3±9.6 yrs.) in primary cardiovascular prevention composed three cohorts: statin users with (SAMS, n=61) or without symptoms (No SAMS, n=15), and controls (n=16). Force (FO), endurance (EN) and power (PO) of the leg extensors (EXT) and flexors (FLE) and handgrip strength (FOHG) were measured using isokinetic and handheld dynamometers, respectively. A 10-point visual analogue scale (VAS) was used to self-assess SAMS intensity. Measures were taken before and after two months of withdrawal.ResultsFollowing withdrawal, repeated-measures analyses show improvements for...

DOAJ (DOAJ: Directory of Open Access Journals), Feb 1, 2022

European Journal of Physical and Rehabilitation Medicine, 2020

BACKGROUND Low back pain is common during pregnancy. Lumbar stabilization and stretching exercise... more BACKGROUND Low back pain is common during pregnancy. Lumbar stabilization and stretching exercises are recommended to treat low back pain in the general population. However, few studies have applied the effects of these two interventions in pregnant women with low back pain. OBJECTIVES To compare the effects of lumbar stabilization and stretching exercises for the treatment of gestational low back pain. DESIGN A pilot randomized clinical trial. SETTING Laboratory of Functional Evaluation and Human Motor Performance and physical therapy clinics. PARTICIPANTS Initially, 30 pregnant women with low back pain were recruited, of which 24 met the following inclusion criteria: being between 19-29 weeks of gestation; being in prenatal clinical follow-up; having nonspecific mechanical low back pain started in pregnancy; not participating in specific low back pain treatment in the last 3 months. A total of 20 women completed the study (10 each group). METHODS The main outcome measures were clinical (pain by Visual Analogue Scale (VAS) and McGill Pain Questionnaire and disability by Roland Morris Questionnaire), and secondary outcome measures were: postural balance (force platform); muscle activation level of multifidus, iliocostalis lumborum, rectus abdominis and external abdominal oblique (electromyography). The women were randomized into 2 groups for 6 weeks of intervention 2 x week for a 50-minute treatment: 1) lumbar stabilization exercise protocol and 2) stretching exercise protocol. RESULTS There was a significant reduction (p = 0.03) in pain (1.68 in VAS and 4.81 for McGill questionnaire) for both interventions, but no change in disability score. In addition, both interventions were comparable for a significant improvement in postural stability (in mean d = 0.77) for the velocity sway parameter, and significantly increased activation (p >0.05) of the external abdominal oblique muscle after intervention. CONCLUSIONS Both modalities (lumbar stabilization and stretching were efficient for pain reduction, improving balance and increasing one trunk activity muscle after 6 weeks of intervention in pregnant women with low back pain. CLINICAL REHABILITATION IMPACT The present study has implications, especially for clinical decision-making in regards to therapy choice in pregnant women with LBP to reduce pain and improve trunk function as measured through balance performance.

Q-PCR analysis for structural proteins. RNA was extracted from 6-month-old mice (5/genotype). Fiv... more Q-PCR analysis for structural proteins. RNA was extracted from 6-month-old mice (5/genotype). Five hundred nanogram of RNA template was used for cDNA synthesis. RT-PCR for (A) β1integrin, (B) β1D integrin, (C) dystrophin and (D) α7integrin was performed using gene-specific primers. (TIF 1186 kb)

β-actin Cre × SLKfl/fl offspring genotype. (DOC 27 kb)

The FASEB Journal, 2014

Objective: To evaluate whether a 12-week supervised exercise program promotes an active lifestyle... more Objective: To evaluate whether a 12-week supervised exercise program promotes an active lifestyle throughout pregnancy in pregnant women with obesity. Methods: In this preliminary randomised trial, pregnant women (body mass index ≥ 30 kg/m2) were allocated to either standard care or supervised training, from 15 to 27 weeks of gestation. Physical activity was measured by accelerometry at 14, 28 and 36 weeks, while fitness (oxygen consumption (VO2) at the anaerobic threshold), nutrition (caloric intake and macronutrients percentage) and anthropometry were assessed at 14 and 28 weeks of gestation. Analyses were performed using repeated measures ANOVA. Results: A total of fifty (50) women were randomised, 25 in each group. There was no time-group interaction for time spent at moderate and vigorous activity (pinteraction = 0.064), but the exercise group’s levels were higher than controls’ at all times (pgroup effect = 0.014). A significant time-group interaction was found for daily physical activity (p = 0.023); similar at baseline ((22.0 ± 6.7 vs 21.8 ± 7.3) x 104 counts/day) the exercise group had higher levels than the control group following the intervention ((22.8 ± 8.3 vs 19.2 ± 4.5) x 104 counts/day, p = 0.020) and at 36 weeks of gestation ((19.2 ± 1.5 vs 14.9 ± 1.5) x 104 counts/day, p = 0.034). Exercisers also gained less weight than controls during the intervention period despite similar nutritional intakes (difference in weight change = -0.1 kg/week, 95% CI -0.2; -0.02, p = 0.016) and improved cardiorespiratory fitness (difference in fitness change = 8.1%, 95% CI 0.7; 9.5, p = 0.041). Conclusions: Compared with standard care, a supervised exercise program allows pregnant women with obesity to maintain fitness, limit weight gain and attenuate the decrease in physical activity levels observed in late pregnancy. Trial Registration: ClinicalTrials.gov NCT01610323

Table 1. All treatments and muscle-specific genetic deletion of RANK did not have an impact on mu... more Table 1. All treatments and muscle-specific genetic deletion of RANK did not have an impact on muscle mass at 5 weeks of age. Table 2. Primers used for PCR amplification and genotyping. Figure 1. RANK deletion reduces EDL muscle damage in 5 week-old mdx mice. Figure 2. Full-length OPG-Fc treatment and RANK deletion protect dystrophic skeletal muscles. Figure 3. RANK deletion protects skeletal muscles in old mdx mice. Figure 4. Full-length OPG-Fc mitigates muscular dystrophy in fast-twitch skeletal muscles. Figure 5. Recovery scores of various key functional parameters of skeletal muscles evaluated ex vivo from dystrophic mice treated with full-length OPG-Fc, anti-RANKL, anti-TRAIL and/or selectively deficient in muscle RANK. Figure 6. Full-length OPG-Fc markedly increases functional performance during eccentric downhill running. Figure 7. Recovery scores of forced and voluntary physical exercise performance in full-length OPG-Fc treated dystrophic mdx mice. Figure 8. Muscle RANK del...