Research"Investigating how hormones regulate skeletal muscle metabolism and renewal"
Our laboratory is dedicated to understanding how cells respond and adapt to stress-induced hormonal changes and how those pathways become inappropriately activated or inhibited in disease. We focus on hormone-induced changes in gene regulation and the impact of those newly expressed genes on skeletal muscle physiology and pathophysiology. |
New Pathways Modulating Insulin Sensitivity in Obesity
Humans require a constant glucose supply to maintain heart and brain function even when food is scarce. However, excess circulating glucose is detrimental and underlies development of type 2 diabetes. In type 2 diabetes, blood glucose becomes too high in part because liver, skeletal muscle and fat become resistant to insulin. “Insulin resistance” occurs in individuals with clinical pre-diabetes, which affects ~30% of adults in the US, most of whom are undiagnosed. In spite of the prevalence of this disease, few FDA approved drugs attack insulin resistance. Thus, there is an urgent need to identify “drug-able” pathways to increase the therapeutic options for pre-diabetes.
Our laboratory studies an enzyme called salt inducible kinase 1 (SIK1) that is present throughout the body and participates in fine-tuning hormonal responses. Our laboratory made the surprising observation that deletion of the Sik1 gene in mice fed a high fat diet allowed the muscles to take in and use more glucose, even though the mice became just as obese as normal mice fed the same diet. We now know that SIK1 is chronically turned up in skeletal muscle of obese mice. Our studies funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIH-NIDDK) and by the American Diabetes Association (ADA) indicate that SIK1 increased in obesity seems to counteract the effects of insulin on muscle glucose utilization. This makes SIK1 a very promising target for therapeutic development. We are currently investigating how the SIK1 enzyme inhibits muscle glucose utilization, focusing on systems within the muscle that produce and use energy (ATP) from glucose.
How Do Hormones Regulate Muscle Regeneration?
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One aspect of aging is loss of skeletal muscle mass and strength, which impacts metabolic health as well maintenance of normal daily activities. Our laboratory is undertaking a multi-faceted approach to identify pathways that could be targeted with drugs to help maintain muscle mass through activation of stem cells that exist in all skeletal muscle, even in adults. The hormone-activated signaling pathways we study (mediated by cAMP) are known to stimulate proliferation and self-renewal of muscle stem cells. However, little is known about which hormone activate this pathway. We have developed tools to characterize how novel factors released by muscle activate muscle stem cells and to study the impact of these pathways on muscle stem cell function, and ultimately muscle mass, during aging. For this project, we created mice in which we can mimic hormonal activation of cAMP signaling using an otherwise inert drug. Using these mice and isolated muscle stem cells, we are working to establish a signature of genes and proteins associated with hormone-activated muscle stem cell activity and muscle regeneration. Finally, we engineered “glow in the dark” reporter mice that glow in the dark when growth-promoting hormonal pathways are activated. Ultimately we expect to uncover new pathways that could be targeted to promote muscle growth and strength in aging individuals.
One aspect of aging is loss of skeletal muscle mass and strength, which impacts metabolic health as well maintenance of normal daily activities. Our laboratory is undertaking a multi-faceted approach to identify pathways that could be targeted with drugs to help maintain muscle mass through activation of stem cells or promotion of growth, or hypertrophy, of existing muscle. First, we are analyzing the effects of SIK1 on muscle mass because SIK1 responds in different ways to hormones that promote muscle growth and to conditions that promote muscle wasting. We are now testing the impact of genetic SIK1 deletion in mice on muscle mass, muscle strength and exercise ability with aging. Second, we have developed tools to characterize how novel factors released by muscle activate muscle stem cells and study the impact of these pathways on muscle stem cell function and ultimately muscle mass during aging. In addition, we created mice in which we can mimic hormonal pathways that stimulate muscle hypertrophy using an otherwise inert chemical compound. Using these mice and isolated muscle stem cells, we are working to establish a signature of genes and proteins associated with muscle stem cell activity and muscle growth. Finally, we engineered reporter mice that glow in the dark when growth-promoting hormonal pathways are activated. Ultimately we expect to uncover new pathways that could be targeted to promote muscle growth and strength in aging individuals. |
Research Projects
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