Xavier Devillard

Molecular Mechanisms of Skeletal Muscle Atrophy in a Mouse Model of Cerebral Ischemia

Background and Purpose— Loss of muscle mass and function is a severe complication in patients with stroke that contributes to promoting physical inactivity and disability. The deleterious consequences of skeletal muscle mass loss underline the necessity to identity the molecular mechanisms involved in skeletal muscle atrophy after cerebral ischemia. Methods— Transient focal cerebral ischemia (60 minutes) was induced by occlusion of the right middle cerebral artery in C57BL/6J male mice. Skeletal muscles were removed 3 days later and analyzed for the regulation of critical determinants of muscle mass homeostasis (Akt/mammalian target of rapamycin pathway, myostatin-Smad2/3 and bone morphogenetic protein-Smad1/5/8 signaling pathways, ubiquitin-proteasome and autophagy-lysosome proteolytic pathways). Results— Cerebral ischemia induced severe sensorimotor deficits associated with muscle mass loss of the paretic limbs. Mechanistically, cerebral ischemia repressed Akt/mammalian target of rapamycin pathway and increased expression of key players of ubiquitin-proteasome pathway (MuRF1 [muscle RING finger-1], MAFbx [muscle atrophy F-box], Musa1 [muscle ubiquitin ligase of SCF complex in atrophy-1]), together with a marked increase in myostatin expression, in both paretic and nonparetic skeletal muscles. The Smad1/5/8 pathway was also activated. Conclusions— Our data fit with a model in which a repression of Akt/mammalian target of rapamycin pathway and an increase in the expression of key players of ubiquitin-proteasome pathway are critically involved in skeletal muscle atrophy after cerebral ischemia. Cerebral ischemia also caused an activation of bone morphogenetic protein-Smad1/5/8 signaling pathway, suggesting that compensatory mechanisms are also concomitantly activated to limit the extent of skeletal muscle atrophy.

The faisability and the effects of cycloergometer interval-training on aerobic capacity and walking performance after stroke. Preliminary study

BACKGROUND After stroke, the early and persistent decline in aerobic capacity leads to diminish walking capacities. The aim of the study is to investigate the effects of aerobic cycloergometer interval-training on the walking performances in subacute and chronic stroke survivors. METHOD A prospective design was used. Fourteen patients whose stroke had occurred more than 3 months and less than 2 years performed an aerobic training session with a cycloergometer for 8 weeks. A maximal exercise test, a 6-min walking test, a 20-m test and an isokinetic muscle strength test were realized before and after training session. RESULTS There was a significant increase after aerobic training in maximal power (Pmax) (mean 23.2%, P<0.0001), in VO(2peak) (mean 14.8%, P=0.04), and in the knee extension and flexion muscle peak torque on the nonparetic side and extension on the paretic side in isokinetic mode (mean from 13 to 29%, P=from 0.019 to P=0.0007) and in the walking performances on the 6-min walk test (mean 15.8%, P=0.0002). CONCLUSION Patients with subacute and chronic stroke can improve aerobic capacity, muscle strength and walking performances after cycloergometer interval-training. Although these results must be interpreted with caution considering the small size of our sample, they suggest that aerobic training is a safe and potentially effective training after stroke and an alternative to walking treadmill training.

Post-transcriptional regulation of autophagy in C2C12 myotubes following starvation and nutrient restoration

In skeletal muscle, autophagy is activated in multiple physiological and pathological conditions, notably through the transcriptional regulation of autophagy-related genes by FoxO3. However, recent evidence suggests that autophagy could also be regulated by post-transcriptional mechanisms. The purpose of the study was therefore to determine the temporal regulation of transcriptional and post-transcriptional events involved in the control of autophagy during starvation (4h) and nutrient restoration (4h) in C2C12 myotubes. Starvation was associated with an activation of autophagy (decrease in mTOR activity, increase in AMPK activity and Ulk1 phosphorylation on Ser467), an increase in autophagy flux (increased LC3B-II/LC3B-I ratio, LC3B-II level and LC3B-positive punctate), and an increase in the content of autophagy-related proteins (Ulk1, Atg13, Vps34, and Atg5-Atg12 conjugate). Our data also indicated that the content of autophagy-related proteins was essentially maintained when nutrient sufficiency was restored. By contrast, mRNA level of Ulk1, Atg5, Bnip3, LC3B and Gabarapl1 did not increase in response to starvation. Accordingly, binding of FoxO3 transcription factor on LC3B promoter was only increased at the end of the starvation period, whereas mRNA levels of Atrogin1/MAFbx and MuRF1, two transcriptional targets of FoxO involved in ubiquitin-proteasome pathway, were markedly increased at this time. Together, these data provide evidence that target genes of FoxO3 are differentially regulated during starvation and that starvation of C2C12 myotubes is associated with a post-transcriptional regulation of autophagy.