Muscle wasting remains a cause of morbidity and mortality after trauma, burns and infection. Although the mechanisms for the atrophic response are multi-factorial and poorly defined, our work during the past funding period documents the causal relationship between the up regulation of inflammatory modulators, particularly TNF? and NO, and the decreased translational control of muscle protein synthesis. Further, we reported that sepsis impairs the responsiveness of skeletal muscle to nutrient (e.g., leucine) stimulation. This leucine (Leu) resistance results from suppression of mTOR kinase activity and inhibition of protein synthesis, and is Akt/TSC-independent. Our long-term goal is to elucidate the cellular and molecular mechanisms by which sepsis down-regulates nutritional signals and produces skeletal muscle myopathy, thereby validating specific proteins as potential therapeutic targets. Specifically, our overall objective is to identify Akt/TSC-independent mechanisms by which sepsis down-regulates nutritional signals and produces skeletal muscle myopathy. To address the questions implicit in this goal, the proposed research has the following specific aims: (1) Assess the importance of the sepsis-induced change in total and/or phosphorylated DEPTOR (a known mTOR negative regulatory protein) as a mechanism for the decrease in basal and/or Leu-stimulated muscle protein synthesis;(2) Determine the mechanism by which sepsis disrupts endosomal trafficking of mTOR complex-1 (mTORC1) and impairs amino acid sensing and protein synthesis in muscle;and (3) Elucidate the extent to which altered MAP4K3 signaling is mechanistically linked to the sepsis-induced decrease in mTORC1 activity under basal and nutrient-stimulated conditions. Our application exploits a number of innovative approaches made possible by the availability of novel reagents and supported by provocative preliminary data. While our focus on state-of-the-art in vivo approaches permits us to definitively assign physiological importance to our observations, complementary in vitro studies will allow us to define cellular mechanisms and to prioritize future work. It is noteworthy that the proposed in vivo electroporation of shRNA or over-expression plasmids specifically to skeletal muscle permits loss- and gain-of-function experiments to be performed, thereby assigning causality to the observed changes. Furthermore, changes in muscle mass/protein synthesis will be correlated with direct assessment of muscle contractility. These in vivo methods, used in conjunction with an established murine model of sepsis and with the availability of novel phospho-specific antibodies, place us in a unique position to rapidly and significantly advance knowledge pertaining to amino acid regulation of mTORC1 in both health and disease. The expected research outcomes will have a positive impact by contributing fundamental knowledge concerning nutrient regulation at the molecular level and providing seminal mechanistic insights into the clinically significant pathology of sepsis-induced myopathy which impedes recovery and rehabilitation.

Public Health Relevance

The loss of skeletal muscle in patients after infection or traumatic injury delays recovery and decreases survival. The reason why this wasting occurs is not fully understood, but it cannot be fully corrected by providing adequate nutrition. Our research will determine the mechanism for this nutritional resistance and the accompanying muscle atrophy, which will have an important positive impact by ultimately leading to the development of novel therapeutic treatments and improved patient outcome.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBIB-X (02))
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Dunsmore, Sarah
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Pennsylvania State University
Schools of Medicine
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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 :
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) Inability to replete white adipose tissue during recovery phase of sepsis is associated with increased autophagy, apoptosis, and proteasome activity. Am J Physiol Regul Integr Comp Physiol 312:R388-R399
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
Atherton, Philip J; Greenhaff, Paul L; Phillips, Stuart M et al. (2016) Control of skeletal muscle atrophy in response to disuse: clinical/preclinical contentions and fallacies of evidence. Am J Physiol Endocrinol Metab 311:E594-604
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
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:
Gordon, Bradley S; Williamson, David L; Lang, Charles H et al. (2015) Nutrient-induced stimulation of protein synthesis in mouse skeletal muscle is limited by the mTORC1 repressor REDD1. J Nutr 145:708-13
Steiner, Jennifer L; Lang, Charles H (2015) Sepsis attenuates the anabolic response to skeletal muscle contraction. Shock 43:344-51
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

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