Impaired Skeletal Muscle Repair after Ischemia-Reperfusion Injury in Mice

Ischemia/reperfusion (IR) injury can induce skeletal muscle fibre death and subsequent regeneration. By 14 days, absolute and specific maximal forces and fatigue resistance in ischemic/reperfused soleus muscles were still reduced (−89%, −81%, and −75%, resp.) as compared to control muscles (P < .05). The decrease of these parameters in ischemic/reperfused muscle was much greater than that of myotoxic injured muscles (−12%, −11%, and −19%; P < .05). In addition, at 14 days ischemic/reperfused muscle structure was still abnormal, showing small muscle fibres expressing neonatal myosin heavy chain and large necrotic muscle fibres that were not observed in myotoxin treated muscles. By 56 days, in contrast to myotoxin treated muscles, specific maximal force and muscle weight of the ischemic/reperfused muscles did not fully recover (P < .05). This differential recovery between ischemic/reperfused and myotoxin treated muscles was not related to the differences in the initial cell death, loss of satellite cells after injury, expression of growth factors (IGF1, IGF2..), or capillary density in regenerating muscles. In conclusion, our results demonstrate that IR injury in mice induces long term detrimental effects in skeletal muscles and that the recovery following IR injury was delayed for yet unknown reasons as compared to myotoxic injury

Downregulation of the Glial GLT1 glutamate transporter and purkinje cell dysfunction in a mouse model of myotonic dystrophy

Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels