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Molecular mechanisms regulation skeletal muscle plasticity ⁄ SNSF
Third-party funded project
Project title Molecular mechanisms regulation skeletal muscle plasticity ⁄ SNSF
Principal Investigator(s) Handschin, Christoph
Organisation / Research unit Departement Biomedizin / Experimental Pharmacology,
Departement Biozentrum / Growth & Development (Handschin)
Project start 01.02.2009
Probable end 30.11.2010
Status Completed
Abstract

Skeletal muscle is the single most abundant tissue in higher animals. Thus, in order to minimize the expenditure for maintenance and maximize functionality, skeletal muscle has an enormous capacity to adapt to various stimuli, e.g., motor nerve activation and contractile activity, nutrient supply, temperature and hypoxia. Altered signaling pathways and changes in metabolic and contractile properties contribute to the phenotypic plasticity of skeletal muscle. The functional units of skeletal muscle, the muscle fibers, vary considerably in their morphological, biochemical and physiological properties. To a considerable extent, skeletal muscle adaptation is achieved by fiber-type switching from the more oxidative, high endurance, slow twitch type I fibers to the glycolytic, low endurance, fast twitch type IIa and IIb fibers and vice versa. In fact, any given muscle consists of a specific proportion of different muscle fibers, according to their respective physiological requirements.

Loss in the ability to adapt or maladaption of skeletal muscle has serious pathophysiological consequences. Early events in the development of type 2 diabetes are insulin-resistance, lipid deposition and other metabolic dysregulation in muscle. Diseases with aberrant proportions of muscle fiber-types include paraplegia, obstructive pulmonary disorder and age-related muscle wasting (sarcopenia). Several muscular dystrophies are caused by defects in NMJ formation or myofibrillar proteins, such as amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy, respectively. For most of these diseases, the underlying molecular mechanisms are unknown.

The outcome of many of these diseases could be improved by stimulating or mimicking the effect of exercise on muscle physiology. Most strikingly, a combination of diet and exercise is more efficient in preventing and treating type 2 diabetes than pharmacological interventions. From a epidemiological perspective, regular doses of physical activity translates to a 30% reduction in stroke, type 2 diabetes and heart disease. Muscle wasting in muscular dystrophies or sarcopenia could similarly be prevented or ameliorated. However, since many of the patients suffering from these diseases are exercise intolerant, further knowledge of the molecular pathways involved in activity-induced muscle plasticity will be important in the development of novel approaches to tackle these disorders. Our projects aims at a functional characterization of the transcriptional coactivator peroxisome proliferator-activated receptor g coactivator 1a (PGC-1a) in skeletal muscle. PGC-1a transcription is strongly regulated by physical activity and muscle diseases are often associated with inadequate levels of PGC-1a.

Financed by Swiss National Science Foundation (SNSF)
   

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29/03/2024