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.
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.
|Rossetti, Michael L; Steiner, Jennifer L; Gordon, Bradley S (2017) Androgen-mediated regulation of skeletal muscle protein balance. Mol Cell Endocrinol 447:35-44|
|Steiner, Jennifer L; Lang, Charles H (2017) Etiology of alcoholic cardiomyopathy: Mitochondria, oxidative stress and apoptosis. Int J Biochem Cell Biol 89:125-135|
|Crowell, Kristen T; Moreno, Samantha; Steiner, Jennifer L et al. (2017) Temporally Distinct Regulation of Pathways Contributing to Cardiac Proteostasis During the Acute and Recovery Phases of Sepsis. Shock :|
|Steiner, Jennifer L; Lang, Charles H (2017) Alcoholic Cardiomyopathy: Disrupted Protein Balance and Impaired Cardiomyocyte Contractility. Alcohol Clin Exp Res 41:1392-1401|
|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; 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|
|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|
|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) Alcohol intoxication following muscle contraction in mice decreases muscle protein synthesis but not mTOR signal transduction. Alcohol Clin Exp Res 39:1-10|
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