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.
|Long, Chengzu; Li, Hui; Tiburcy, Malte et al. (2018) Correction of diverse muscular dystrophy mutations in human engineered heart muscle by single-site genome editing. Sci Adv 4:eaap9004|
|Papizan, James B; Vidal, Alexander H; Bezprozvannaya, Svetlana et al. (2018) Cullin-3-RING ubiquitin ligase activity is required for striated muscle function in mice. J Biol Chem 293:8802-8811|
|Amoasii, Leonela; Olson, Eric N; Bassel-Duby, Rhonda (2018) Control of Muscle Metabolism by the Mediator Complex. Cold Spring Harb Perspect Med 8:|
|Makarewich, Catherine A; Baskin, Kedryn K; Munir, Amir Z et al. (2018) MOXI Is a Mitochondrial Micropeptide That Enhances Fatty Acid ?-Oxidation. Cell Rep 23:3701-3709|
|Polster, Alexander; Nelson, Benjamin R; Papadopoulos, Symeon et al. (2018) Stac proteins associate with the critical domain for excitation-contraction coupling in the II-III loop of CaV1.1. J Gen Physiol 150:613-624|
|Zhang, Yu; Long, Chengzu; Li, Hui et al. (2017) CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. Sci Adv 3:e1602814|
|Makarewich, Catherine A; Olson, Eric N (2017) Mining for Micropeptides. Trends Cell Biol 27:685-696|
|Baskin, Kedryn K; Makarewich, Catherine A; DeLeon, Susan M et al. (2017) MED12 regulates a transcriptional network of calcium-handling genes in the heart. JCI Insight 2:|
|Zhou, Huanyu; Morales, Maria Gabriela; Hashimoto, Hisayuki et al. (2017) ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression. Genes Dev 31:1770-1783|
|Papizan, James B; Garry, Glynnis A; Brezprozvannaya, Svetlana et al. (2017) Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice. J Clin Invest 127:3730-3740|
Showing the most recent 10 out of 58 publications