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 #
5R01DK015658-41
Application #
8332245
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
2012-08-01
Budget End
2013-07-31
Support Year
41
Fiscal Year
2012
Total Cost
$342,673
Indirect Cost
$117,673
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Miller, William P; Mihailescu, Maria L; Yang, Chen et al. (2016) The Translational Repressor 4E-BP1 Contributes to Diabetes-Induced Visual Dysfunction. Invest Ophthalmol Vis Sci 57:1327-37
Steiner, Jennifer L; Kimball, Scot R; Lang, Charles H (2016) Acute Alcohol-Induced Decrease in Muscle Protein Synthesis in Female Mice Is REDD-1 and mTOR-Independent. Alcohol Alcohol 51:242-50
Gordon, Bradley S; Steiner, Jennifer L; Williamson, David L et al. (2016) Emerging role for regulated in development and DNA damage 1 (REDD1) in the regulation of skeletal muscle metabolism. Am J Physiol Endocrinol Metab 311:E157-74
Kimball, Scot R; Gordon, Bradley S; Moyer, Jenna E et al. (2016) Leucine induced dephosphorylation of Sestrin2 promotes mTORC1 activation. Cell Signal 28:896-906
Grainger, Deborah L; Kutzler, Lydia; Rannels, Sharon L et al. (2016) Validation of a commercially available anti-REDD1 antibody using RNA interference and REDD1-/- mouse embryonic fibroblasts. F1000Res 5:250
Gordon, Bradley S; Williamson, David L; Lang, Charles H et al. (2015) Nutrient-induced stimulation of protein synthesis in mouse skeletal muscle is limited by the mTORC1 repressor REDD1. J Nutr 145:708-13
So, Jae-Seon; Cho, Sungyun; Min, Sang-Hyun et al. (2015) IRE1α-Dependent Decay of CReP/Ppp1r15b mRNA Increases Eukaryotic Initiation Factor 2α Phosphorylation and Suppresses Protein Synthesis. Mol Cell Biol 35:2761-70
Kelleher, Andrew R; Pereira, Suzette L; Jefferson, Leonard S et al. (2015) REDD2 expression in rat skeletal muscle correlates with nutrient-induced activation of mTORC1: responses to aging, immobilization, and remobilization. Am J Physiol Endocrinol Metab 308:E122-9
Steiner, Jennifer L; Crowell, Kristen T; Kimball, Scot R et al. (2015) Disruption of REDD1 gene ameliorates sepsis-induced decrease in mTORC1 signaling but has divergent effects on proteolytic signaling in skeletal muscle. Am J Physiol Endocrinol Metab 309:E981-94
Dennis, Michael D; Kimball, Scot R; Fort, Patrice E et al. (2015) Regulated in development and DNA damage 1 is necessary for hyperglycemia-induced vascular endothelial growth factor expression in the retina of diabetic rodents. J Biol Chem 290:3865-74

Showing the most recent 10 out of 170 publications