Skeletal muscle dysfunction in acquired and inherited diseases
Our team develops a translational research to better understand the involvement of skeletal muscle in the physiopathology of acquired (Type 2 diabetes, Chronic Obstructive Pulmonary Disease, Chronic Kidney Disease) and inherited (Facioscapulohumeral Distrophy) diseases. Our team is a leading expert in clinical and fundamental research in the fields of inflammation, oxidative stress and muscle regeneration, and therefore, we have developed innovative study models such as human tissue biopsies and primary cultures of muscle and adipose stem cells.
In recent years the incidence of obesity and related metabolic disorders has increased significantly, obesity is now considered a pandemic. In France, in 2014, 33% of the adult population is overweight [25 kg / m ≤ BMI (body mass index: weight / height) <30 kg / m] and 15% is obese [BMI> 30 kg / m ] (ObEpi-Roche, 2012) and 4 million people have diabetes.
Chronic Obstructive Pulmonary Disease (COPD) is a respiratory disease characterized by significant systemic, extra-pulmonary, manifestations that contribute to patient survival prognosis. Peripheral muscle dysfunction is an important systemic consequence in COPD as it is involved in exercise intolerance, poor quality of life and reduced survival. Deconditioning was the initially proposed mechanism to explain the development of muscle dysfunction in COPD, but there is accumulating evidence that other potential factors are also involved such as oxidative stress, inflammation and malnutrition. In the past 5 years, we have contributed to the increased knowledge in this topic by developing translational studies in COPD, from classical clinical, including pulmonary rehabilitation, to more fundamental research at the cellular and molecular level.
Summary: Oxidative stress and inflammation, which are linked via amplification loops, are cornerstones in the pathophysiology of malnutrition-inflammation complex syndrome (MICS), contributing to worsen the outcome of chronic kidney disease (CKD) patients. Skeletal muscle and vascular smooth muscle cells appear as main targets of MICS. Indeed, skeletal muscle dysfunction in uremia has been characterized by a reduction in exercise tolerance and lean body mass (LBM) wasting appearing as an active phenomenon.
Our project is focused on three objectives :
1) to develop creatinine metabolism as a clinically available biomarker of muscle wasting and dysfunction. 2) to characterize and modulate (through changes of oxidative stress and inflammation parameters) the phenotypic skeletal muscle changes related to CKD and evaluate the effects of exercise training, benefiting the facilities and similar experimental design as previously used in the chronic obstructive pulmonary disease topic. 3) to understand the involvement of oxidative stress and inflammation in uremia-related vascular calcifications.
Facioscapulohumeral muscular dystrophy (FSHD), the most common inherited muscle disease of adult life in Europe, is an autosomal dominant disease characterized by progressive weakness and atrophy of specific skeletal muscles.
Despite major progress in the understanding of the genetic basis of FSHD, the exact mechanisms that lead to FSHD defects are not completely understood and no curative treatment is available. However, there is growing evidence that oxidative stress may contribute to FSHD pathology. Collectively, our data support the role of oxidative stress and the value of an anti-oxidant strategy adapted to the FSHD-specific “oxidative stress”. Indeed, our previous results show that vitamins and minerals may improve skeletal muscle function in patients with FSHD. Our major goal is to determine the precise mechanisms and targets involved in this effect. Our general objective is to create a synergy between basic and clinical research by assessing the effects of therapeutic supplementation with antioxidants and/or rehabilitation on muscle disease.
During skeletal muscle regeneration, the processes controlling the maintenance of cell immaturity and the transitions from immature muscle stem cells (IMSC) into commited skeletal muscle cells are extremely important. These cell fate decisions thus influence the quality of cell therapy strategies. In this context, our research projects aim to identify the molecular and cellular mechanisms that govern the heterogeneity and survival of muscle stem cells in order to maximize their ability to regenerate human muscle tissues.
Total Publications Team # III (from 2014). (to see).