Binge drinking and chronic alcohol abuse (i.e. alcoholism) represent important public health issues as these are associated with high risk behaviors, multiple organ system dysfunction, impaired recovery from illness and even premature death. Habitual alcohol abuse leads to skeletal muscle myopathy characterized by muscle loss, weakness, and decreased physical function. These symptoms are associated with molecular changes including a depressed rate of mTOR-dependent protein synthesis in skeletal muscle. Few treatment strategies exist to aid in the recovery from this disease both in the continued presence of alcohol and under circumstances where abstinence is achieved. However, skeletal muscle contraction activates mTOR kinase activity and increases protein synthesis. Importantly, when an intermittent contractile stimulus is sustained over several weeks it induces significant muscle growth and a coordinate increase in muscle function. Therefore, stimulated muscle contraction, either voluntarily or via transcutaneous electrical stimulation, may represent a potential therapeutic modality for individuals with alcoholic muscle disease who have limited mobility and functional capacity. Our long term goal is to determine the effects of alcohol on skeletal muscle protein synthesis and mTOR activity that has been increased by stimulated muscle contraction, and to identify potential signaling changes and new proteins that mediate the observed response. Progression towards this goal will be achieved through the following specific aims: (1) Determine whether acute alcohol intoxication reverses the pre-existing increase in mTOR activity, protein synthesis and muscle hypertrophy induced by acute or chronic muscle contraction;(2) Establish the therapeutic relevance of acute and chronic muscle contraction in a model of chronic alcoholic myopathy with regards to changes in muscle mTOR activity, protein synthesis and muscle hypertrophy;(3) Define the role of endosomal/lysosomal targeting of TSC2 and mTOR following acute and chronic alcohol, and muscle contraction relevant to previously observed changes in hypertrophy, contractility and mTOR signaling;and (4) Identify skeletal muscle proteins whose synthetic rate is altered by alcohol and/or muscle contraction using puromycin-associated nascent chain proteomics (PUNCH- P).
These aims represent a set of novel and comprehensive experiments utilizing several innovative in vivo and ex vivo techniques including rodent models of acute and chronic alcohol abuse, isolated muscle strength and fatigability testing, visualization of the molecular trafficking of mTOR and TSC2, as well as mass spectrometry to identify newly made proteins following alcohol and muscle contraction. Data garnered from these experiments will provide clinically relevant knowledge to significantly advance treatment strategies and contribute to the mechanistic understanding of the etiology of acute and chronic alcoholic muscle disease.

Public Health Relevance

Intake of excessive amounts of alcohol either acutely (i.e., binge drinking), or over a prolonged time period are detrimental to health and represent a major public health issue. The goal of this research study is to determine the underlying etiology for how acute and chronic alcohol abuse alters muscle protein balance and to determine whether muscle contraction is an effective therapy to treat and improve recovery from alcoholic muscle disease. New targets for future research and treatment development will also be discovered through these projects and this should improve current treatment modalities and accelerate recovery of functional deficits induced by alcohol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AA023422-01
Application #
8779998
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Orosz, Andras
Project Start
2014-07-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Hershey
State
PA
Country
United States
Zip Code
17033
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
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
Steiner, Jennifer L; Crowell, Kristen T; Lang, Charles H (2015) Impact of Alcohol on Glycemic Control and Insulin Action. Biomolecules 5:2223-46
Steiner, Jennifer L; Lang, Charles H (2015) Alcohol intoxication following muscle contraction in mice decreases muscle protein synthesis but not mTOR signal transduction. Alcohol Clin Exp Res 39:1-10
Farrag, Mohamed; Laufenberg, Lacee J; Steiner, Jennifer L et al. (2015) Modulation of voltage-gated Ca2+ channels by G protein-coupled receptors in celiac-mesenteric ganglion neurons of septic rats. PLoS One 10:e0125566
Steiner, Jennifer L; Pruznak, Anne M; Navaratnarajah, Maithili et al. (2015) Alcohol Differentially Alters Extracellular Matrix and Adhesion Molecule Expression in Skeletal Muscle and Heart. Alcohol Clin Exp Res 39:1330-40
Steiner, Jennifer L; Lang, Charles H (2015) Sepsis attenuates the anabolic response to skeletal muscle contraction. Shock 43:344-51
Steiner, Jennifer L; Gordon, Bradley S; Lang, Charles H (2015) Moderate alcohol consumption does not impair overload-induced muscle hypertrophy and protein synthesis. Physiol Rep 3:
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
Steiner, Jennifer L; Lang, Charles H (2015) Dysregulation of skeletal muscle protein metabolism by alcohol. Am J Physiol Endocrinol Metab 308:E699-712

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