Many signal transduction pathways have been implicated in control of myogenic specification and differentiation during development and postnatal skeletal muscle growth. It has also become increasingly clear that such developmental programs are recapitulated during repair of adult skeletal muscle by resident muscle stem cells, or satellite cells. Thus, a thorough understanding of signal transduction pathways that promote myogenic differentiation could lead to the development of new therapeutics to promote muscle repair or growth in a variety of human pathologic states. The second messenger cAMP and its cellular effectors are dynamically regulated during muscle development, but little is known about the specific targets of cAMP that mediates its effects in muscle cells. To address this question, we focus on cAMP-induced transcriptional pathways that affect myogenic differentiation and skeletal muscle repair. We identified one such transcriptional target, Salt- Inducible Kinase 1 (SIK1), which is an enzyme that catalyzes phosphorylation of class II histone deacetylases and allows expression of muscle specific genes. Sik1 mRNA is expressed in developing somites and SIK1 function is important for survival of myocytes and skeletal muscle in mice. However, little is known about how the enzyme itself is regulated in undifferentiated myoblasts, whether its function is required during muscle development, or whether Sik1 deletion in myofibers will cause myopathy. The proposed experiments will test the hypothesis that SIK1 induction is required for appropriate timing of MEF2 activity during myogenic differentiation and muscle repair. We will investigate molecular determinants of SIK1 stability and test whether this regulatory mechanism is important for limiting MEF2 activity in undifferentiated myoblasts. We will also test the hypothesis that SIK1 regulation of class II HDACs is a crucial step during myoblast differentiation by examining differentiation of primary myoblasts lacking Sik1 and by characterizing phenotypes in mice with satellite cell-specific deletion of Sik1. A corollary to this hypothesis is that SIK1 activity is required for full muscle fiber development or repair. This hypothesis will be tested in mice lacking Sik1 expression in myogenic precursor cells and differentiated myofibers. Our genetic strategy will allow unequivocal determination of the cell type in which SIK1 acts to promote muscle repair. The data resulting from these experiments will establish whether SIK1 is necessary for myogenic differentiation and muscle repair and will reveal the molecular mechanisms by which this enzyme is normally regulated in skeletal myoblasts. As a target of cAMP signaling, SIK1 is a signal-dependent modulator of the myogenic program. SIK1 or its regulators could serve as therapeutic targets to promote skeletal muscle regeneration and repair in human patients.
The proposed studies will investigate the regulation and functions of an enzyme (SIK1) that responds to hormonal signals and regulates skeletal muscle differentiation. Therapeutic agents that activate this pathway prevent muscle atrophy in several human disease conditions, including disuse atrophy and muscular dystrophy, but these drugs have deleterious side effects. By understanding how SIK1 specifically functions in developing and adult skeletal muscle, we aim to establish it as a new molecular target for therapeutic agents that could be used to more specifically combat muscle degeneration with less side effects on other tissues.
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| Kim, Eun Ran; Fan, Shengjie; Akhmedov, Dmitry et al. (2017) Red blood cell ?-adrenergic receptors contribute to diet-induced energy expenditure by increasing O2 supply. JCI Insight 2: |
| Nixon, Mark; Stewart-Fitzgibbon, Randi; Fu, Jingqi et al. (2016) Skeletal muscle salt inducible kinase 1 promotes insulin resistance in obesity. Mol Metab 5:34-46 |
| Akhmedov, Dmitry; Rajendran, Kavitha; Mendoza-Rodriguez, Maria G et al. (2016) Knock-in Luciferase Reporter Mice for In Vivo Monitoring of CREB Activity. PLoS One 11:e0158274 |
| Wong, Ching-On; Palmieri, Michela; Li, Jiaxing et al. (2015) Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction. Cell Rep 12:2009-20 |
| Clark, Rebecca I; Tan, Sharon W S; Péan, Claire B et al. (2013) MEF2 is an in vivo immune-metabolic switch. Cell 155:435-47 |
| Fu, Jingqi; Akhmedov, Dmitry; Berdeaux, Rebecca (2013) The short isoform of the ubiquitin ligase NEDD4L is a CREB target gene in hepatocytes. PLoS One 8:e78522 |
| Chatterjee, Somik; Nam, Deokhwa; Guo, Bingyan et al. (2013) Brain and muscle Arnt-like 1 is a key regulator of myogenesis. J Cell Sci 126:2213-24 |
| Akhmedov, Dmitry; Berdeaux, Rebecca (2013) The effects of obesity on skeletal muscle regeneration. Front Physiol 4:371 |
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