Obesity and associated disorders, including metabolic syndrome, type 2 diabetes, and hyperlipidemia, are systemic abnormalities that result from aberrant metabolism, energy utilization and signaling between tissues. Skeletal muscle plays a central role in the control of whole-body metabolism, energy homeostasis and insulin sensitivity. In addition, skeletal muscle serves as a source of secreted peptide hormones and cytokines, referred to as myokines that act in an endocrine manner to control metabolism, inflammation and other processes. While the importance of myokines is becoming increasingly apparent, much remains to be learned about the identities of these factors, the mechanisms that control their expression and their mechanisms of action. Recently, we discovered that a family of muscle-specific microRNAs (miRNAs) control systemic energy homeostasis and myofiber diversity. These miRNAs, called MyomiRs, exert their actions by repressing the expression of a collection of transcription factors that regulate gene programs involved in metabolic control and fiber type switching. Among the most dominant targets of the MyomiRs is Med13, a component of the Mediator complex, which acts as a regulatory hub for transcriptional control. Mediator subunits have been implicated in numerous aspects of metabolism through regulation of nuclear hormone receptor signaling. However, the functions of Med13 and other Mediator subunits in skeletal muscle have not been explored. Our studies suggest that MyomiRs together with Med13 (and possibly other Mediator subunits) establish a regulatory circuit in striated muscle that influences systemic energy balance and metabolism. We have discovered several myokines that are regulated during myofiber switching. The overall goals of this project are designed to decipher the upstream mechanisms whereby MyomiRs and Mediator subunits govern myokine production, to elucidate the mechanisms of action of these molecules, and to define their roles in skeletal muscle adaptations to activity and disease. The project is based on an extensive foundation of preliminary work from our group, as well as numerous genetically modified mice in which the MyomiR-Mediator-Myokine pathways have been modulated through gain- and loss-of-function approaches. Ultimately, we hope to use these insights to develop new strategies to therapeutically modulate myokine signaling as a means of normalizing metabolism in settings of obesity, diabetes and metabolic syndrome.
Skeletal muscle plays a fundamental role in systemic energy homeostasis and metabolism. Its role as an endocrine tissue and source of biologically active metabolic regulators has only recently been appreciated. The existence of systemic muscle-derived regulators provides new possibilities for studying activities of skeletal muscle that regulate whole body metabolism with the long-term goal of providing novel strategies for prevention or treatment of obesity, metabolic syndrome, and associated disorders, such as atherosclerosis and type 2 diabetes.
|Olson, Eric N (2014) MicroRNAs as therapeutic targets and biomarkers of cardiovascular disease. Sci Transl Med 6:239ps3|
|Lee, Ji-Hoon; Bassel-Duby, Rhonda; Olson, Eric N (2014) Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila. Proc Natl Acad Sci U S A 111:9491-6|
|Porrello, Enzo R; Olson, Eric N (2014) A neonatal blueprint for cardiac regeneration. Stem Cell Res 13:556-70|
|Mahmoud, Ahmed I; Porrello, Enzo R; Kimura, Wataru et al. (2014) Surgical models for cardiac regeneration in neonatal mice. Nat Protoc 9:305-11|
|Nam, Young-Jae; Lubczyk, Christina; Bhakta, Minoti et al. (2014) Induction of diverse cardiac cell types by reprogramming fibroblasts with cardiac transcription factors. Development 141:4267-78|
|Schober, Andreas; Nazari-Jahantigh, Maliheh; Wei, Yuanyuan et al. (2014) MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat Med 20:368-76|
|Munshi, Nikhil V; Olson, Eric N (2014) Translational medicine. Improving cardiac rhythm with a biological pacemaker. Science 345:268-9|
|Aurora, Arin B; Porrello, Enzo R; Tan, Wei et al. (2014) Macrophages are required for neonatal heart regeneration. J Clin Invest 124:1382-92|
|Garg, Ankit; O'Rourke, Jason; Long, Chengzu et al. (2014) KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy. J Clin Invest 124:3529-39|
|Aurora, Arin B; Olson, Eric N (2014) Immune modulation of stem cells and regeneration. Cell Stem Cell 15:14-25|
Showing the most recent 10 out of 16 publications