Sébastien S. Dufresne

A 12-Week Exercise Program for Pregnant Women with Obesity to Improve Physical Activity Levels: An Open Randomised Preliminary Study

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

Osteoprotegerin protects against muscular dystrophy.

Receptor-activator of NF-κB, its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology still is elusive. Here, we show that muscle cells can produce and secrete osteoprotegerin and pharmacologic treatment of dystrophic mdx mice with recombinant osteoprotegerin muscles. (Recombinant osteoprotegerin-Fc mitigates the loss of muscle force in a dose-dependent manner and preserves muscle integrity, particularly in fast-twitch extensor digitorum longus.) Our data identify osteoprotegerin as a novel protector of muscle integrity, and it potentially represents a new therapeutic avenue for both muscular diseases and osteoporosis.

Muscle RANK is a key regulator of Ca2+ storage, SERCA activity, and function of fast-twitch skeletal muscles.

Receptor-activator of nuclear factor-κB (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(2+)sensor, and altered activity of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) modulating Ca(2+)storage. Muscle RANK deletion had no significant effects on the sham or denervated slow-twitch soleus muscles. These data identify a novel role for RANK as a key regulator of Ca(2+)storage and SERCA activity, ultimately affecting denervated skeletal muscle function.

Nucleoside Triphosphate Diphosphohydrolase-1 Ectonucleotidase Is Required for Normal Vas Deferens Contraction and Male Fertility through Maintaining P2X1 Receptor Function

Background: NTPDase1 hydrolyzes ATP, which is the agonist of the P2X1 receptor. Results: NTPDase1 is expressed in vas deferens smooth muscles and regulates its contraction and spermatozoa concentration in the semen. Conclusion: NTPDase1 controls male fertility via the regulation of P2X1 activation. Significance: This mechanism may unveil a cause of infertility in males and open a new therapeutic area. In this work, we report that Entpd1−/− mice, deficient for the ectonucleotidase nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), produce smaller litters (27% reduction) compared with wild-type C57BL6 animals. This deficit is linked to reduced in vivo oocyte fertilization by Entpd1−/− males (61 ± 11% versus 88 ± 7% for Entpd1+/+). Normal epididymal sperm count, spermatozoa morphology, capacitation, and motility and reduced ejaculated sperm number (2.4 ± 0.5 versus 3.7 ± 0.4 million for Entpd1+/+) pointed to vas deferens dysfunction. NTPDase1 was localized by immunofluorescence in the tunica muscularis of the vas deferens. Its absence resulted in a major ATP hydrolysis deficiency, as observed in situ by histochemistry and in primary smooth muscle cell cultures. In vitro, Entpd1−/− vas deferens displayed an exacerbated contraction to ATP, a diminished response to its non-hydrolysable analog αβMeATP, and a reduced contraction to electrical field stimulation, suggesting altered P2X1 receptor function with a propensity to desensitize. This functional alteration was accompanied by a 3-fold decrease in P2X1 protein expression in Entpd1−/− vas deferens with no variation in mRNA levels. Accordingly, exogenous nucleotidase activity was required to fully preserve P2X1 receptor activation by ATP in vitro. Our study demonstrates that NTPDase1 is required to maintain normal P2X1 receptor functionality in the vas deferens and that its absence leads to impaired peristalsis, reduced spermatozoa concentration in the semen, and, eventually, reduced fertility. This suggests that alteration of NTPDase1 activity affects ejaculation efficacy and male fertility. This work may contribute to unveil a cause of infertility and open new therapeutic potentials.

Investigation of wild-type and mycolactone-negative mutant Mycobacterium ulcerans on skeletal muscle: IGF-1 protects against mycolactone-induced muscle catabolism

Buruli ulcer (BU), which is caused by Mycobacterium ulcerans (MU), is an endemic and neglected tropical disease that affects mostly subcutaneous tissues. Skeletal muscle under infected skin is also subject to serious dysfunctions and contractures. The goal of this study was to investigate the effects of an infection with the wild-type M. ulcerans (WT-MU) or the mycolactone-negative Mycobacterium ulcerans (M(neg)-MU) mutant strains on myotubes or fully differentiated skeletal muscles. WT-MU infection decreased by 22% and 29% the maximal muscle force at days 7 and 42 postinfection, respectively, while M(neg)-MU induced no decrease at day 7 postinfection and a small but significant 13% decrease in muscle force at day 42. A 13.2-fold and 4.3-fold increase in neutrophil and macrophage concentrations, respectively, was observed on day 42 following the injection of WT-MU. However, the increases in neutrophil and macrophage concentrations were 2.4-fold and 5.5-fold in M(neg)-MU. Myoblast proliferation decreased by 20%, myotube diameter by 45%, MyHC levels by 32%, while MuRF-1 levels increased by 22.8% when C2C12 cells and WT-MU were cocultured for 48 h at a multiplicity of infection of 5:1. In contrast, M(neg)-MU had no significant effect. Interestingly, the addition of 1,000 ng/ml of IGF-1 to the WT-MU/C2C12 coculture significantly improved all of these biological parameters. The present investigation clearly established that muscle dysfunction and chronic inflammation in the presence of WT-MU are largely caused by the release of mycolactone, and the addition of recombinant IGF-1 was sufficient to alleviate some of the antiproliferative and atrophic effects of mycolactone.

Osteoprotegerin and β2-Agonists Mitigate Muscular Dystrophy in Slow- and Fast-Twitch Skeletal Muscles

Our recent work showed that daily injections of osteoprotegerin (OPG)-immunoglobulin fragment complex (OPG-Fc) completely restore the function of fast-twitch extensor digitorum longus muscles in dystrophic mdx mice, a murine model of Duchenne muscular dystrophy. However, despite marked improvements, OPG-Fc was not as effective in preventing the loss of function of slow-twitch soleus and diaphragm muscles. Because β2-agonists enhance the function of slow- and fast-twitch dystrophic muscles and because their use is limited by their adverse effects on bone and cardiac tissues, we hypothesized that OPG-Fc, a bone and skeletal muscle protector, acts synergistically with β2-agonists and potentiates their positive effects on skeletal muscles. We observed that the content of β2-adrenergic receptors, which are mainly expressed in skeletal muscle, is significantly reduced in dystrophic muscles but is rescued by the injection of OPG-Fc. Most important, OPG-Fc combined with a low dose of formoterol, a member of a new generation of β2-agonists, histologically and functionally rescued slow-twitch dystrophic muscles. This combination of therapeutic agents, which have already been tested and approved for human use, may open up new therapeutic avenues for Duchenne muscular dystrophy and possibly other neuromuscular diseases.

Galectin-3 and N-acetylglucosamine promote myogenesis and improve skeletal muscle function in the mdx model of Duchenne muscular dystrophy

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), in which mutations in the dystrophin gene disrupts the firm adhesion. In patients with DMD, even moderate contraction causes damage, leading to progressive muscle degeneration. The damaged muscles are repaired through myogenesis. Consequently, myogenesis is highly active in patients with DMD, 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 the myogenesis. Galectin‐3 is an oligosaccharide‐binding protein and is known to be involved in cell–cell interactions and cell–matrix interactions. Galectin‐3 is expressed in myoblasts and skeletal muscle, although its function in muscle remains elusive. In this study, we found evidence that galectin‐3 and the monosaccharide N‐acetylglucosamine, which increases the synthesis of binding partners (oligosaccharides) of galectin‐3, promote myogenesis in vitro. Moreover, in the mdx mouse model of DMD, treatment with N‐acetylglucosamine increased muscle‐force production. The results suggest that treatment with N‐acetylglucosamine might mitigate the burden of DMD.—Rancourt, A., Dufresne, S. S., St‐Pierre, G., Levesque, J.‐C., Nakamura, H., Kikuchi, Y., Satoh, M. S., Frenette, J., Sato, S. Galectin‐3 and N‐acetylglucosamine promote myogenesis and improve skeletal muscle function in the mdx model of Duchenne muscular dystrophy. FASEB J. 32, 6445–6455 (2018). www.fasebj.org

Impact of Inflammation and Anti-inflammatory Modalities on Skeletal Muscle Healing: From Fundamental Research to the Clinic

Anti-inflammatory modalities are commonly used for the treatment of various musculoskeletal injuries. Although inflammation was originally believed to interfere with skeletal muscle regeneration, several recent studies have highlighted the beneficial effects of inflammatory cells on muscle healing. This discrepancy is attributable to an evolving understanding of the complex inflammatory process. To better appreciate the paradoxical roles of inflammation, clinicians must have a better comprehension of the fundamental mechanisms regulating the inflammatory response. In this perspective article, cellular, animal, and human studies were analyzed to summarize recent knowledge regarding the impact of inflammation on muscle regeneration in acute or chronic conditions. The effect of anti-inflammatory drugs on the treatment of various muscle injuries was also considered. Overall, this work aims to summarize the current state of the literature on the inflammatory process associated with muscle healing in order to give clinicians the necessary tools to have a more efficient and evidence-based approach to the treatment of muscle injuries and disorders.

Physiological role of receptor activator nuclear factor-kB (RANK) in denervation-induced muscle atrophy and dysfunction.

The bone remodeling and homeostasis are mainly controlled by the receptor-activator of nuclear factor kB (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 (RANKmko) 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 RANKmko 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 Ca2+ influx following the depletion of SR Ca2+ stores, were markedly higher in denervated RANKmko EDL muscles. We speculated that extracellular Ca2+ influx mediated by STIM-1 may be important for the increase in [CaT] and the gain of force in denervated RANKmko 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.