Anatomical and mesoscopic characterization of the dystrophic diaphragm: An in vivo nuclear magnetic resonance imaging study in the Golden retriever muscular dystrophy dog.

Because respiratory failure remains a major issue in Duchenne Muscular Dystrophy patients, respiratory muscles are a key target of systemic therapies. In the Golden Retriever Muscular Dystrophy (GRMD) dogs, the disease shows strong clinical and histological similarities with the human pathology, making it a valuable model for preclinical therapeutic trials. We report here the first nuclear magnetic resonance (NMR) imaging anatomical study of the diaphragm in GRMD dogs and healthy controls. Both T1- and T2-weighted images of the diaphragm of seven healthy and thirteen GRMD dogs, from 3 to 36 months of age, were acquired on a 3 tesla NMR scanner. Abnormalities of texture and shape were revealed and consisted of increases in signal intensity on T2-weighted images and in signal heterogeneity on both T1- and T2-weighted images of the dystrophic diaphragm. These abnormalities were associated with a significant thickening of the muscle and we identified a clear 8-mm-threshold distinguishing clinically preserved GRMD dogs from those more severely affected. In this study, we demonstrated the feasibility of NMR imaging of the diaphragm and depicted several anatomical and mesoscopic anomalies in the dystrophic diaphragm. NMR imaging of the diaphragm shows a promise as an outcome measure in preclinical trials using GRMD dogs.

Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy.

Sepsis, or systemic inflammatory response syndrome, is the major cause of critical illness resulting in admission to intensive care units. Sepsis is caused by severe infection and is associated with mortality in 60% of cases. Morbidity due to sepsis is complicated by neuromyopathy, and patients face long-term disability due to muscle weakness, energetic dysfunction, proteolysis and muscle wasting. These processes are triggered by pro-inflammatory cytokines and metabolic imbalances and are aggravated by malnutrition and drugs. Skeletal muscle regeneration depends on stem (satellite) cells. Herein we show that mitochondrial and metabolic alterations underlie the sepsis-induced long-term impairment of satellite cells and lead to inefficient muscle regeneration. Engrafting mesenchymal stem cells improves the septic status by decreasing cytokine levels, restoring mitochondrial and metabolic function in satellite cells, and improving muscle strength. These findings indicate that sepsis affects quiescent muscle stem cells and that mesenchymal stem cells might act as a preventive therapeutic approach for sepsis-related morbidity.