During this reporting period the Laboratory of Genetics and Physiology has made progress in the understanding of mechanisms used by cytokines to control the physiology of muscle and the involvement of cytokines in regulating metabolic processes. Muscle composition and metabolism STAT5 in the muscle is required for postnatal growth and glucose homeostasis, indicating that STAT5 controls the maintenance of muscle mass and function. Histological and gene profiling data revealed reduced muscle mass, an alteration in fiber type composition and decreased activity in mice with a muscle-specific deletion of STAT5 (MKO). This was most pronounced in the quadriceps, a muscle that is composed almost exclusively of type II fibers. This muscle displayed increased expression of type I fiber genes and de novo appearance of type I fibers in mice with muscle-specific deletion of STAT5. We were able to identify the androgen receptor as the critical gene whose expression is regulated directly by STAT5. This demonstrates a novel link between growth hormone signaling, androgen action in muscle cells and muscle physiology. Fatty acid oxidation in muscle Analysis of STAT5 regulated transcription in muscle tissue further revealed a role of STAT5 in fatty acid oxidation as the expression of several genes were found to depended on STAT5. STAT5 MKO female mice revealed decreased body weight, lean mass and soleus weight at 2.5 months old. However, the mice showed increased body weight, lean mass, quadriceps and soleus weight at 20 months old. Stat5 MKO female mice revealed increased fat mass and body fat accumulation at 20 months old. Fatty acid oxidation rate in soleus was increased at 2.5 months old, but it was decreased at 20 months old in STAT5 MKO female mice. STAT5 MKO male mice also revealed increased fat mass and body fat accumulation at 20 months old. Those mice also revealed decreased fatty acid oxidation rate in soleus. We propose that a decrease in fatty acid oxidation contributes to the increased fat mass and body fat accumulation in old mice. We are currently investigating the specific mechanisms involved in the regulation of these processes and the metabolic consequences of signaling events that are regulated by the transcription factor STAT5.
| Hosui, Atsushi; Kimura, Akiko; Yamaji, Daisuke et al. (2009) Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-{beta} and STAT3 activation. J Exp Med 206:819-31 |
| Klover, Peter; Chen, Weiping; Zhu, Bing-Mei et al. (2009) Skeletal muscle growth and fiber composition in mice are regulated through the transcription factors STAT5a/b: linking growth hormone to the androgen receptor. FASEB J 23:3140-8 |
