Sphingosine-1-phosphate analog FTY720 reverses obesity but not age-induced anabolic resistance to muscle contraction

Authors: RIVAS, DONATO - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; RICE, NICHOLAS - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; EZZYAT, YASSINE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MCDONALD, DEVIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; COOPER, BRITTANY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FIELDING, ROGER - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: American Journal of Physiology - Cell Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/20/2019
Publication Date: 8/27/2019
Citation: Rivas, D., Rice, N., Ezzyat, Y., McDonald, D.J., Cooper, B.E., Fielding, R.A. 2019. Sphingosine-1-phosphate analog FTY720 reverses obesity but not age-induced anabolic resistance to muscle contraction. American Journal of Physiology - Cell Physiology. 317:C502-C512. https://doi.org/10.1152/ajpcell.00455.2018.
DOI: https://doi.org/10.1152/ajpcell.00455.2018

Interpretive Summary: Sarcopenia is the age-associated loss of skeletal muscle mass that is paired with declines in physical functioning, leading to higher rates of disability, frailty, morbidity, and mortality. Aging and obesity independently contribute to the loss of muscle mass that is assumed to be a result of the activation of mutual physiological pathways. Understanding mechanisms contributing to the induction of skeletal muscle loss with aging and obesity is important for determining targets that may have pivotal roles in muscle loss in these conditions. We find that aging and obesity equally induce the inability to turn on growth pathways in response to skeletal muscle contraction. Furthermore, treatment with a drug (FTY720) that inhibits production of toxic types of fats for 4 weeks increased lean mass, strength, and the muscle growth responses to contraction in obese, but not older, animals. To determine the role of high amounts of inflammation and different fats on muscle growth, we increased a molecule that controls inflammation (IKKbeta) with and without exposure to different types of fats: saturated (SFA), polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids. We found that high amounts of IKKbeta increased inflammation markers in muscle cells, and this high inflammation exacerbated loss of muscle growth in response to SFA. Treatment with FTY720 reversed the inflammatory effects of PA in the muscle cells. Taken together, these data demonstrate that high inflammation can induce the loss of muscle growth. SFA aggravates these effects and FTY720 can reverse this by decreasing toxic fat accumulation in skeletal muscle.

Technical Abstract: Sarcopenia, the age-associated loss of skeletal muscle mass and function, is coupled with declines in physical functioning leading to subsequent higher rates of disability, frailty, morbidity, and mortality. Aging and obesity independently contribute to muscle atrophy that is assumed to be a result of the activation of mutual physiological pathways. Understanding mechanisms contributing to the induction of skeletal muscle atrophy with aging and obesity is important for determining targets that may have pivotal roles in muscle loss in these conditions. We find that aging and obesity equally induce an anabolic resistance to acute skeletal muscle contraction as observed with decreases in anabolic signaling activation after contraction. Furthermore, treatment with the sphingosine-1-phosphate analog FTY720 for 4 wk increased lean mass and strength, and the anabolic signaling response to contraction was improved in obese but not older animals. To determine the role of chronic inflammation and different fatty acids on anabolic resistance in skeletal muscle cells, we overexpressed IKKbeta with and without exposure to saturated fatty acid (SFA; palmitic acid), polyunsaturated fatty acid (eicosapentaenoic acid), and monounsaturated fatty acid (oleic acid). We found that IKKbeta overexpression increased inflammation markers in muscle cells, and this chronic inflammation exacerbated anabolic resistance in response to SFA. Pretreatment with FTY720 reversed the inflammatory effects of palmitic acid in the muscle cells. Taken together, these data demonstrate chronic inflammation can induce anabolic resistance, SFA aggravates these effects, and FTY720 can reverse this by decreasing ceramide accumulation in skeletal muscle.