Research Projects

Main Research Topics of Skeletal muscle biology:

General aims:

1. Regulation of muscle fiber-types:
   Many aspects of skeletal muscle plasticity are controlled by the proportion of fibers with different muscle fiber-types, e.g., type I, oxidative, slow twitch muscle fibers vs. type II, glycolytic, fast-twitch fibers. Interestingly, these fiber types also differ in other aspects of muscle biology such as their insulin-sensitivity, response to exercise and resistance to atrophy and dystrophy. The transcriptional coactivator PGC-1α is a strong driver of fiber type switching towards oxidative muscle fibers (Lin et al. 2002 Nature). We investigate the molecular mechanisms underlying the different responses of muscle fiber types to physiological and pathophysiological states.
   
   
2. Mitochondrial function and dysfunction in skeletal muscle:
   Proper mitochondrial function is essential for maintaining normal muscle physiology. Decreased expression levels of mitochondrial genes as well as the transcriptional coactivators PGC-1α and PGC-1β have been found in skeletal muscle biopsies of type 2 diabetic patients (Mootha et al. 2003 Nat Genet, Patti et al. 2003 Proc Natl Acad Sci USA). We are studying the implications of PGC-1 dysregulation in skeletal muscle and the causality of this defect on glucose homeostasis in muscle-specific gain- and loss-of-function PGC-1α animal models.
    
   
3. Molecular mechanisms in muscle atrophy and dystrophy
   PGC-1α coordinately controls the expression of metabolic, myofibrillar and neuromuscular junction genes and thus integrates the response of skeletal muscle to increased physical demand. In disuse or denervation, transcript levels of PGC-1α decrease. Interestingly, ectopic expression of PGC-1α in skeletal muscle can prevent muscle atrophy due to hind limb denervation (Sandri et al. 2006 Proc Natl Acad Sci USA). We are elucidating the mechanisms by which PGC-1α controls muscle fiber size and could be used as a therapeutic target in muscle atrophy or dystrophies in patients.

Methodological approaches: 

• General molecular and biochemical techniques
• Tissue culture of immortalized cell lines and primary muscle cells
• Light and fluorescent microscopy
• Mouse models (muscle-specific PGC-1 transgenic mice, muscle-specific PGC-1α knockout animals)
• Mouse phenotyping: treadmill running, grip strength, metabolic analysis, indirect calorimetry, Dexa scanning, histology, etc.
• Expression analysis: RNA (including real-time PCR, cDNA expression arrays) and protein
• Genomic approaches (e.g. global screening of transcription factor expression levels)
• Bioinformatics (e.g., identification of transcription factor binding sites, see Podvinec et al. 2002 Mol Endocrinol, Mootha et al. 2004 Proc Natl Acad Sci USA)