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Regulation of Muscle Energy Production and Strength in Diabetes

November 2021

In September 2021, Brian T. O’Neill, Assistant Professor in Internal Medicine and member of FOEDRC, published a paper in the Journal of Clinical Investigation that shows how insulin and the closely related insulin-like growth factor-1 (IGF-1) work in muscle to regulate energy production in mitochondria by suppressing the activation of FoxO transcription factors.

Decreased muscle strength and muscle atrophy are features of long-standing or uncontrolled diabetes that can worsen with aging or bedrest after surgery. Reduced muscle mass and decreased activity increases the risk for premature death. The mechanisms that lead to muscle weakness in diabetes are not well known.  In collaboration with Dr. E. Dale Abel, Dr. Vitor Lira, and Dr. William Sivitz from the FOEDRC, Dr. O’Neill demonstrated that loss of insulin and IGF-1 signaling through insulin receptors (IR) and IGF-1 receptors (IGF1R) in muscle led to decreased mitochondrial function, decreased  energy production in the form of ATP, and muscle weakness.  Using mouse and cell models for loss of IR and/or IGF1R, they showed that these mitochondrial defects are mediated by FoxO transcription factors, in part by their ability to reduce the expression of  important mitochondrial genes that govern mitochondrial oxygen consumption and ATP production.  Indeed, when FoxOs were genetically absent, muscle ATP production was normal and muscle strength was restored.  This work identifies FoxOs as important mediators of the detrimental effects of uncontrolled diabetes on muscle function, and may lead to strategies or therapies to improve rehabilitation and recovery from surgery or severe illness for patients with diabetes.

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