Skeletal muscle secreted myonectin prevents frailty and maintains systemic lipid homeostasis.
Description: Sedentary lifestyles and western dietary patterns are major modifiable risk factors of cardiovascular diseases and the associated metabolic comorbidities. Lifestyle intervention with regular exercise is effective in prevention and treatment of these diseases. However, the capability for strenuous exercise training is often limited, especially in elderly patients with sarcopenia and cardiovascular complications. Thus, definition of the molecular mechanisms and development of interventions for modulating skeletal muscle-mediated metabolic regulation are needed. We recently found myonectin, a myokine, is essential for maintaining metabolic homeostasis. We propose to define the physiological function of myonectin and elucidate the mechanisms that control myonectin expression in skeletal muscle. We hypothesize that, myonectin deficiency impairs muscle function and systemic metabolic homeostasis by decreasing muscle lipid utilization, and myonectin expression is regulated by activity-dependent changes in cytosolic calcium signaling. AIM I. To define the role of myonectin in muscle lipid utilization. The autocrine effect of myonectin will be determined by treating myonectin-deficient muscle with recombinant myonectin and vehicle control. The physiological role of myonectin in muscle function and lipid metabolism will be studied in myonectin-deficient mice compared to the wild-type littermate controls. AIM II. To identify the activity-dependent pathway that regulates muscle myonectin expression. The role of calcium in regulating the expression of myonectin will be studied using a mouse model with enhanced muscle calcium handling and increased myonectin expression. The calcium signaling pathways will be interrogated with a series of loss-of-function studies using small molecule inhibitors and dominant-negative vectors compared to the respective vehicle controls. Skeletal muscle secreted myonectin has been suggested to contribute to the protective effects of exercise against cardiovascular disease associated metabolic comorbidities. This study is designed to elucidate the physiological roles for myonectin in skeletal muscle function and in systemic metabolic regulation with the murine models of myonectin deficiency. With the unique models of muscle calcium handling alterations, we will evaluate the role of calcium in regulating myonectin expression to identify pathways to stimulate myonectin expression in a translational context.
Funder: American Heart Association
Amount: $51,900
Funding type: training
Funder scheme: Predoctoral Fellowship
Start date: 2017-01-01
End date: 2018-12-31
Investigators: HUI WANG, HUI WANG
Institution: Baylor College of Medicine
Funded outputs count: 1
Funder award ID: 17PRE33411184
OpenAlex ID: G2385496568