Our long-term goal is to understand how the control of protein synthesis in skeletal muscle can be manipulated for preventive and therapeutic purposes. The objective here is to gain an understanding of how to prevent and/or reverse inactivity-induced loss of skeletal muscle mass. Inactivity encompasses a number of conditions that lead to loss of muscle mass including sedentary life styles, chronic bed rest, casting, limb suspension, and immobilization. Each of these inactivity-related conditions is thought to share a common feature, i.e. a delayed and reduced magnitude in the response of skeletal muscle protein synthesis to an anabolic stimulus, which has been referred to as anabolic resistance. Our central hypothesis is that dysregulation of the mammalian target of rapamycin complex 1 (mTORC1) and/or protein synthetic control mechanisms is the underlying cause of the anabolic resistance-induced loss of skeletal muscle mass. Our hypothesis has been formulated on the basis of our past accomplishments in defining the regulation of mTORC1 signaling and protein synthesis in skeletal muscle under a variety of physiological and pathophysiological conditions. To test our hypothesis, we will pursue an experimental protocol in which control rats and rats subjected to short-term unilateral hindlimb immobilization will be placed on a meal-feeding regimen designed to elicit the anabolic resistance of protein synthesis in skeletal muscle. We will then perform a detailed analysis of components of the mTORC1 signaling pathway, including novel upstream inputs such as p53 and Sestrin 1, 2, and 3, as well as selected novel regulatory mechanisms that mediate control of protein synthesis, including truncated 4E-BP1 and PDCD4. We will also define the regulation and function of two previously identified potential therapeutic targets for manipulating skeletal muscle protein synthesis, i.e. the mTORC1 repressor, regulated in development and DNA damage responses (REDD1) and the growth regulatory protein, eukaryotic initiation factor (eIF2B)?. The proposed studies encompass the following three specific aims: (1) assess responses of the mTORC1 signaling pathway and selected regulatory mechanisms that mediate control of protein synthesis under conditions that elicit anabolic resistance in skeletal muscle;(2) delineate the mechanism of action of REDD1 and define its potential as a therapeutic target for the regulation of mTORC1;and (3) delineate the molecular mechanisms that mediate degradation of eIF2B? and continue to evaluate its therapeutic potential as a regulator of skeletal muscle mass. Overall, we expect the proposed research to reveal molecular targets that can likely be manipulated pharmacologically resulting in new and innovative approaches to the prevention and treatment of muscle wasting conditions.

Public Health Relevance

The loss of skeletal muscle mass due to inactivity, disease, and aging is a widespread phenomenon that can lead to reduced functional strength and mobility, increased fatigability, and increased insulin resistance. Inactivity encompasses a number of conditions that lead to loss of muscle mass including sedentary life styles, chronic bed rest, casting, limb suspension, and immobilization. Each of these inactivity- related conditions is thought to share a common feature, i.e. a delayed and reduced magnitude in the response of skeletal muscle protein synthesis to an anabolic stimulus, which has been referred to as anabolic resistance. The goal of the research proposed here is first to identify the underlying cause of anabolic resistance, and, in doing so, reveal molecular targets that can be manipulated pharmacologically resulting in new and innovative approaches to the prevention and treatment of muscle wasting conditions;and second, to define the regulation and function of two previously identified potential therapeutic targets for manipulating skeletal muscle protein synthesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK015658-42
Application #
8520282
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Laughlin, Maren R
Project Start
1977-09-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
42
Fiscal Year
2013
Total Cost
$330,634
Indirect Cost
$113,509
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Kelleher, Andrew R; Gordon, Bradley S; Kimball, Scot R et al. (2014) Changes in REDD1, REDD2, and atrogene mRNA expression are prevented in skeletal muscle fixed in a stretched position during hindlimb immobilization. Physiol Rep 2:e00246
Gordon, Bradley S; Steiner, Jennifer L; Lang, Charles H et al. (2014) Reduced REDD1 expression contributes to activation of mTORC1 following electrically induced muscle contraction. Am J Physiol Endocrinol Metab 307:E703-11
Dennis, Michael D; Coleman, Catherine S; Berg, Arthur et al. (2014) REDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling. Sci Signal 7:ra68
Williamson, David L; Li, Zhuyun; Tuder, Rubin M et al. (2014) Altered nutrient response of mTORC1 as a result of changes in REDD1 expression: effect of obesity vs. REDD1 deficiency. J Appl Physiol (1985) 117:246-56
Martin, Tony D; Dennis, Michael D; Gordon, Bradley S et al. (2014) mTORC1 and JNK coordinate phosphorylation of the p70S6K1 autoinhibitory domain in skeletal muscle following functional overloading. Am J Physiol Endocrinol Metab 306:E1397-405
Fort, Patrice E; Losiewicz, Mandy K; Pennathur, Subramaniam et al. (2014) mTORC1-independent reduction of retinal protein synthesis in type 1 diabetes. Diabetes 63:3077-90
Kimball, Scot R (2014) Integration of signals generated by nutrients, hormones, and exercise in skeletal muscle. Am J Clin Nutr 99:237S-242S
Steiner, Jennifer L; Pruznak, Anne M; Deiter, Gina et al. (2014) Disruption of genes encoding eIF4E binding proteins-1 and -2 does not alter basal or sepsis-induced changes in skeletal muscle protein synthesis in male or female mice. PLoS One 9:e99582
Gordon, Bradley S; Kazi, Abid A; Coleman, Catherine S et al. (2014) RhoA modulates signaling through the mechanistic target of rapamycin complex 1 (mTORC1) in mammalian cells. Cell Signal 26:461-7
Dennis, Michael D; McGhee, Nora K; Jefferson, Leonard S et al. (2013) Regulated in DNA damage and development 1 (REDD1) promotes cell survival during serum deprivation by sustaining repression of signaling through the mechanistic target of rapamycin in complex 1 (mTORC1). Cell Signal 25:2709-16

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