Influenza A pneumonia is the most common cause of death from an infectious agent in older patients. While the lung is the primary target of the influenza A virus, the resulting illness is characterized by dysfunction in multiple organs. Skeletal muscle weakness is an important manifestation of the systemic consequences of influenza A virus infection (IAV) and is manifest in approximately half of the patients admitted to the intensive care unit with respiratory failure. This weakness can persist for years after hospital discharge and it is a major contributor to morbidity. We present preliminary data suggesting that endocrine signals released from the injured lung both induce and protect against skeletal muscle dysfunction during influenza A infection. We hypothesize that the frailty of the proteostasis networks in the muscles of aged mice shifts this balance, resulting in enhanced skeletal muscle dysfunction. Thus, we propose via three interrelated aims, to elucidate the signaling pathways regulating skeletal muscle degradation and proteostasis during influenza A pneumonia:
in Specific Aim # 1, we propose to determine whether influenza A infection causes disruption in muscle proteostasis via IL-6, STAT3, FOXO3 and atrogin1 dependent degradation of skeletal muscle;
in Specific Aim # 2, we propose to assess whether in aged mice influenza A infection causes AMPK activation and thus inhibition of mTOR which leads to impaired proliferation/differentiation of satellite cells and recovery and in Specific Aim # 3, we will determine whether modulating the chaperone response can improve muscle function in aged mice. We have conducted experiments for each of the specific aims, and the preliminary data support the feasibility of this proposal. Completion of the proposed research will provide novel, clinically relevant information regarding the effects of influenza A infection on myoproteostasis. This novel information is of biologic and clinical relevance and should lead to the design of innovative approaches to improve proteostasis and skeletal muscle function in older patients with influenza A infection.

Public Health Relevance

It is not required per instructions stated on the Funding Opportunity Announcement PAR-13-258, Section IV. Application and Submission Information, Project, Research & Related Other Project Information (Project), ?Project Narrative: Do not complete?.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG049665-01
Application #
8855156
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2015-07-01
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Shigemura, Masahiko; Lecuona, Emilia; Sznajder, Jacob I (2017) Effects of hypercapnia on the lung. J Physiol 595:2431-2437
Makinde, Hadijat M; Cuda, Carla M; Just, Talia B et al. (2017) Nonclassical Monocytes Mediate Secondary Injury, Neurocognitive Outcome, and Neutrophil Infiltration after Traumatic Brain Injury. J Immunol 199:3583-3591
Folmsbee, Stephen Sai; Gottardi, Cara J (2017) Cardiomyocytes of the Heart and Pulmonary Veins: Novel Contributors to Asthma? Am J Respir Cell Mol Biol 57:512-518
Gonzalez-Gonzalez, Francisco J; Chandel, Navdeep S; Jain, Manu et al. (2017) Reactive oxygen species as signaling molecules in the development of lung fibrosis. Transl Res 190:61-68
Reczek, Colleen R; Birsoy, K?vanç; Kong, Hyewon et al. (2017) A CRISPR screen identifies a pathway required for paraquat-induced cell death. Nat Chem Biol 13:1274-1279
Magnani, Natalia D; Dada, Laura A; Queisser, Markus A et al. (2017) HIF and HOIL-1L-mediated PKC? degradation stabilizes plasma membrane Na,K-ATPase to protect against hypoxia-induced lung injury. Proc Natl Acad Sci U S A 114:E10178-E10186
Ceco, Ermelinda; Weinberg, Samuel E; Chandel, Navdeep S et al. (2017) Metabolism and Skeletal Muscle Homeostasis in Lung Disease. Am J Respir Cell Mol Biol 57:28-34
Zheng, Zhikun; Chiu, Stephen; Akbarpour, Mahzad et al. (2017) Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction. Sci Transl Med 9:
Subramanian, Kanagaraj; Rauniyar, Navin; Lavalleé-Adam, Mathieu et al. (2017) Quantitative Analysis of the Proteome Response to the Histone Deacetylase Inhibitor (HDACi) Vorinostat in Niemann-Pick Type C1 disease. Mol Cell Proteomics 16:1938-1957
Fernandez, Ramiro; Chi, Monica; Ison, Michael G et al. (2017) Sequelae of Donor-derived Mollicutes Transmission in Lung Recipients. Am J Respir Crit Care Med 195:687-689

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