An understanding of the regulation of protein metabolism in skeletal muscle is required for the development of rational approaches to the treatment of diabetes mellitus and other disease states that affect nutrient homeostasis. Toward this end, the overall goal of this project is to gain a better understanding of the mechanisms by which hormones and nutrients regulate the pathway of protein synthesis in skeletal muscle. The specific focus of the project continues to be on translational control, particularly the regulation of initiation of protein synthesis. In the next grant period, special attention is to be given to the mechanism of action of insulin on specific initiation factors, particularly eIF-2 and eIF-2B. Furthermore, the regulatory role of amino acids is to be investigated because of the recent demonstration of their importance in controlling protein synthesis in skeletal muscle in humans. Additionally, the project is to be extended from skeletal to cardiac muscle so as to better contrast the variations in translational control manifested by muscles composed of different fiber types.
The specific aims of the project are: (1) to develop monospecific antibodies and cDNA clones to individual subunits of initiation factors that are found to be important in the regulation of protein synthesis in muscle; (2) to investigate protein and mRNA expression as well as structure/function relationships of specific initation factors in muscle using monospecific antibodies and cDNA clones; (3) to investigate the mechanism by which insulin stimulates initiation of protein synthesis and causes an enhancement of eIF-2B activity in muscle; (4) to identify in skeletal muscle the specific initiation factor(s) involved in regulation of initiation of protein synthesis by amino acids and hormones other than insulin; and (5) to identify in cardiac muscle the specific initiation factor(s) involved in the regulation of initiation of protein synthesis by fatty acids and other oxidizable noncarbohydrate substrates. Overall , the studies described in this proposal should help to identify mechanisms by which hormones and nutrients regulate protein synthesis in skeletal and cardiac muscle. They should also provide new insights into the biochemical and molecular mechanisms involved in the initiation of protein synthesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK015658-25
Application #
2136933
Study Section
Metabolism Study Section (MET)
Project Start
1977-09-01
Project End
1996-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
25
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Dai, Weiwei; Miller, William P; Toro, Allyson L et al. (2018) Deletion of the stress-response protein REDD1 promotes ceramide-induced retinal cell death and JNK activation. FASEB J :fj201800413RR
Kimball, Scot R (2017) Leucine-Induced Upregulation of Terminal Oligopyrimidine mRNA Translation in Skeletal Muscle: Just the Tip of the Iceberg? J Nutr 147:1603-1604
Pettit, Ashley P; Jonsson, William O; Bargoud, Albert R et al. (2017) Dietary Methionine Restriction Regulates Liver Protein Synthesis and Gene Expression Independently of Eukaryotic Initiation Factor 2 Phosphorylation in Mice. J Nutr 147:1031-1040
Gordon, Bradley S; Liu, Chang; Steiner, Jennifer L et al. (2016) Loss of REDD1 augments the rate of the overload-induced increase in muscle mass. Am J Physiol Regul Integr Comp Physiol 311:R545-57
Black, Adam J; Gordon, Bradley S; Dennis, Michael D et al. (2016) Regulation of protein and mRNA expression of the mTORC1 repressor REDD1 in response to leucine and serum. Biochem Biophys Rep 8:296-301
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
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
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
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

Showing the most recent 10 out of 175 publications