Muscle wasting is a hallmark of sustained alcohol abuse and the associated weakness represents the most common form of skeletal muscle myopathy. Over the past 4 years we have used genetic, biochemical and pharmacological approaches, both in vivo and in vitro, to generate definitive evidence pertaining to the mechanisms by which acute alcohol intoxication (binge drinking) and chronic alcohol consumption impair muscle protein synthesis under basal postabsorptive conditions and antagonize the anabolic response to amino acids and growth factors. The original 3 aims remain valid with experiments in the first phase of the R37 elucidating the cellular mechanisms by which alcohol down-regulates nutritional signals transduced via mTORC1-dependent and -independent transduction networks producing skeletal muscle myopathy, and comparing these to hormone- and contraction-induced regulation. Exceptional progress was made (27 publications) and the research environment leveraged for the successful training and F32 funding of a post- doctoral fellow who will continue in alcohol-related research. Our publications attest that the original aims have been largely achieved; although our new data also open previously unrecognized avenues of exploration. Unique tools have been developed that will permit us to identify and explore novel mechanisms and thereby validate specific proteins as therapeutic targets.
Specific Aim 1 determined whether alcohol-induced changes in Deptor are responsible for the decrease in basal and leucine-stimulated muscle protein synthesis.
This aim i s now extended to investigate the relative importance of alcohol-induced changes in Deptor under in vivo conditions using our newly developed muscle-specific Deptor knockout mouse. Further, our new data reveal alcohol decreases the previously unrecognized binding of REDD1 with Deptor, a finding that will be expanded upon.
Specific Aim 2 delineated the mechanism by which alcohol alters mTOR endosomal trafficking thereby impairing mTORC1 and protein synthesis.
This aim will be continued by assessing alcohol-induced changes, with and without leucine, on Sestrin2 phosphorylation and binding with proteins of the GATOR2 complex. The goal of these experiments is to identify new components and modifiers governing the topology of mTORC1.
Specific Aim 3 elucidated whether altered MAP4K3 signaling is in part responsible for alcohol-induced decreases mTORC1. These studies will be extended to examine the MAP4K3-dependent phosphorylation of Raptor that can function by mTORC1-dependent and -independent mechanisms. This R37 extension exploits innovative approaches, made possible by the availability of novel reagents and supported by our strong track record. While in vitro studies permit us to define cellular mechanisms and prioritize future work, state-of-the-art in vivo approaches permit us to definitively assign physiological importance ? thus filling knowledge gaps. The expected outcomes will contribute translational knowledge on nutrient regulation and provide seminal mechanistic insights into the clinically significant pathology of alcohol-induced muscle disease.

Public Health Relevance

Alcohol excess, both chronic abuse and acute intoxication, exacts a staggering economic cost to society and remains a major public health problem. Alcohol use disorder is associated not only with increased mortality, but also with premature and preventable health concerns, and impaired rehabilitation. Our study focuses on the cellular and molecular mechanisms by which excess alcohol impairs basal skeletal muscle protein synthesis and produces a resistance to the normal beneficial effects of nutrients, thereby leading to the development of alcoholic myopathy, one of the most prominent muscle diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AA011290-22
Application #
9320058
Study Section
Special Emphasis Panel (NSS)
Program Officer
Gao, Peter
Project Start
2017-04-05
Project End
2022-03-31
Budget Start
2017-04-05
Budget End
2018-03-31
Support Year
22
Fiscal Year
2017
Total Cost
$349,425
Indirect Cost
$124,425
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Kimball, Scot R; Lang, Charles H (2018) Mechanisms Underlying Muscle Protein Imbalance Induced by Alcohol. Annu Rev Nutr 38:197-217
Speacht, Toni L; Krause, Andrew R; Steiner, Jennifer L et al. (2018) Combination of hindlimb suspension and immobilization by casting exaggerates sarcopenia by stimulating autophagy but does not worsen osteopenia. Bone 110:29-37
Mekheal, Marina; Steiner, Jennifer L; Lang, Charles H (2018) Acute alcohol prevents the refeeding-induced decrease in autophagy but does not alter the increased protein synthetic response in heart. Alcohol 73:79-88
Steiner, Jennifer L; Lang, Charles H (2017) Alcohol, Adipose Tissue and Lipid Dysregulation. Biomolecules 7:
Steiner, Jennifer L; Lang, Charles H (2017) Etiology of alcoholic cardiomyopathy: Mitochondria, oxidative stress and apoptosis. Int J Biochem Cell Biol 89:125-135
Steiner, Jennifer L; Lang, Charles H (2017) Alcoholic Cardiomyopathy: Disrupted Protein Balance and Impaired Cardiomyocyte Contractility. Alcohol Clin Exp Res 41:1392-1401
Hong-Brown, Ly Q; Brown, C Randell; Navaratnarajah, Maithili et al. (2017) FoxO1-AMPK-ULK1 Regulates Ethanol-Induced Autophagy in Muscle by Enhanced ATG14 Association with the BECN1-PIK3C3 Complex. Alcohol Clin Exp Res 41:895-910
Cannon, Abigail R; Morris, Niya L; Hammer, Adam M et al. (2016) Alcohol and inflammatory responses: Highlights of the 2015 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 54:73-7
Crowell, Kristen T; Steiner, Jennifer L; Coleman, Catherine S et al. (2016) Decreased Whole-Body Fat Mass Produced by Chronic Alcohol Consumption is Associated with Activation of S6K1-Mediated Protein Synthesis and Increased Autophagy in Epididymal White Adipose Tissue. Alcohol Clin Exp Res 40:1832-45
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

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