Muscle wasting remains a cause of morbidity and mortality after trauma, burns and infection. While the cellular mechanisms responsible for the erosion of lean body mass remain poorly defined, a clear causal relationship exists between the up-regulation of inflammatory modulators and decreased translational control of muscle protein synthesis. This sepsis-induced decrease in muscle protein synthesis, resulting at least in part from inhibition of mTOR activity, is manifested under basal conditions and in response to nutrient (e.g., leucine) stimulation. Sepsis also decreases the circulating and bioavailable zinc2+ (Zn), and Zn concentrations have been positively correlated with protein synthesis in non-muscle tissues. Our long-term goal is to define the cellular and molecular mechanisms by which sepsis-induced disruption of Zn homeostasis leads to aberrant protein metabolism and muscle deconditioning. I hypothesize that depletion of Zn in the circulation and the redistribution of Zn within tissues (including skeletal muscle) are partially responsible for the reduction in muscle protein synthesis under basal and nutrient (leucine)-stimulated conditions by impairing mTOR signaling caused by the exacerbation of the local and systemic synthesis of proinflammatory immunomodulators. Overall, these changes are anticipated to lead to a loss of muscle mass and contractile function, and to impair structural and functional recovery in skeletal muscle. To address the questions implicit in this hypothesis, the proposed research has the following specific aims: (1) Elucidate the extent to which the sepsis-induced decrease in circulating Zn is causally related to the impairment in basal and nutrient-stimulated muscle protein synthesis;(2) Determine whether repletion of circulating Zn during sepsis will improve skeletal muscle contractile function;and (3) Determine the mechanism by which a septic insult (LPS/IFNg) disrupts Zn homeostasis under in vitro conditions in myotubes and thereby regulates protein synthesis. While the focus on state-of-the-art in vivo approaches permits us to definitively assign physiological importance to our observations, complementary in vitro studies permit cellular mechanisms to be defined and future work to be prioritized. Furthermore, changes in muscle mass/protein synthesis will be correlated with direct assessment of muscle contractility, adding further translational relevance. These in vivo methods, used in conjunction with established murine models of sepsis and sub-clinical Zn deficiency, and the availability of all reagents needed to quantitate the Zn homeostatic network, place me in a unique position to rapidly and significantly advance knowledge pertaining to the role of this micronutrient in regulating mTOR in skeletal muscle. Thus, not only will the complementary studies and approaches proposed provide an exceptional training program but the research outcomes will contribute fundamental knowledge concerning nutrient regulation at the molecular level and provide seminal mechanistic insights into the clinically significant pathology of sepsis-induced myopathy which impedes recovery and rehabilitation.
The loss of skeletal muscle in patients after infection or trauma delays recovery and decreases long-term survival. Although the underlying cause for this abnormality is not fully understood, it may be related to the concomitant reduction in the concentration of the micronutrient zinc in the circulation and/or skeletal muscle. Our research will determine the mechanism by which the mild zinc deficiency observed in septic patients leads to a reduction in muscle protein synthesis under basal conditions and stimulation by amino acids. We proposed that these defects decrease the ability of muscle to contract and function optimally. Such information will fill a void in our understanding of sepsis-induced muscle atrophy, which will have an important positive impact by ultimately leading to the development of novel therapeutic treatments and improved patient outcome.
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|Crowell, Kristen T; Phillips, Brett E; Kelleher, Shannon L et al. (2017) Immune and metabolic responses in early and late sepsis during mild dietary zinc restriction. J Surg Res 210:47-58|
|Crowell, Kristen T; Soybel, David I; Lang, Charles H (2017) Restorative Mechanisms Regulating Protein Balance in Skeletal Muscle During Recovery From Sepsis. Shock 47:463-473|
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|Crowell, Kristen T; Kelleher, Shannon L; Soybel, David I et al. (2016) Marginal dietary zinc deprivation augments sepsis-induced alterations in skeletal muscle TNF-? but not protein synthesis. Physiol Rep 4:|
|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; 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; Crowell, Kristen T; Lang, Charles H (2015) Impact of Alcohol on Glycemic Control and Insulin Action. Biomolecules 5:2223-46|