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Muscle cell plasticity, myokines and inflammation.
Third-party funded project |
Project title |
Muscle cell plasticity, myokines and inflammation. |
Principal Investigator(s) |
Handschin, Christoph
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Organisation / Research unit |
Departement Biomedizin / Pharmakologie (Handschin), Departement Biozentrum / Growth & Development (Handschin) |
Project start |
01.12.2010 |
Probable end |
30.11.2013 |
Status |
Completed |
Abstract |
Skeletal muscle cells exhibit an enormous plasticity when challenged with different stimuli such as changes in the levels of physical activity, temperature, oxygen, nutrient availability and composition. An intrinsic inadequacy or inability of muscle cells to properly adapt has serious health consequences. Similarly, insufficient usage of skeletal muscle, either imposed by lifestyle choices common in Western societies or by disease states, is a strong and independent risk factor for many chronic disorders including obesity, type 2 diabetes, osteoporosis, cardiovascular diseases, neurological pathologies and certain cancers. Despite the obvious importance of exercise on human health, our knowledge regarding the molecular mechanisms that underlie muscle cell plasticity remains rudimentary. Furthermore, even less is known about the signaling pathways by which an active skeletal muscle improves the function of almost every other organ or inversely, how an inactive muscle triggers the pathological changes which lead to diseases that affect non-muscle tissue. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is the molecular nexus of muscle fiber adaptation to exercise. Elevation of PGC-1α levels in muscle is sufficient to confer a high endurance phenotype. In contrast, genetic ablation of PGC-1α significantly reduces endurance capacity and affects the physiological function of distal organs. Moreover, mice with aberrant PGC-1α expression in muscle exhibit abnormal levels of circulating cytokines, in particular of interleukin 6 (IL-6) and tumor necrosis factor α (TNFα). Interestingly, some of these cytokines have also been described as myokines, signaling factors that are produced and released from contracting muscle, which then act in an auto-, para- and endocrine manner. Our research project aims at delineating and integrating the molecular pathways centered on PGC-1α that control muscle cell plasticity in the active and inactive muscle. First, we will investigate how substrate metabolism is temporally coordinated in the trained muscle where the generation of detrimental side products is avoided. Second, we will study how dysregulated anabolic and catabolic pathways result in increased production of pro-inflammatory cytokines that subsequently modulate the function of muscle and distal organs. Finally, we are interested in the molecular crosstalk between exercise-linked and inflammatory gene expression. These studies will reveal important insights on the mechanisms that regulate muscle cell plasticity and the inter-organ crosstalk in active vs. sedentary individuals. |
Financed by |
Swiss National Science Foundation (SNSF)
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14/05/2024
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