Abstract
Influenza (flu) infection increases the risk for disability, falls, and broken bones in older adults. We have employed a preclinical model to examine the impact of flu on muscle function, which has a direct impact on fall risk. In mice, flu causes mobility and strength impairments with induction of inflammatory and muscle degradation genes that are increased and prolonged with aging. To determine if vaccination could reduce flu-induced muscle decrements, mice were vaccinated with flu nucleoprotein, infected, and muscle parameters were measured. Vaccination of aged mice resulted in significant protection from functional decrements, muscle gene expressions alterations, and morphological damage. Vaccination also improved protection from lung localized and systemic inflammation in aged mice. Despite documented decreased vaccine efficacy with aging, vaccination still provided partial protection to aged mice and represents a potential strategy to prevent flu-induced disability. These findings provide translational insight on ways to reduce flu-induced disability with aging.
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References
Augusto V, Padovani CR, Campos GR. Skeletal muscle fiber types in C57BL6J mice. Braz J Morphol Sci. 2004;21(2):89–94. https://doi.org/10.1055/s-00040444.
Baazim H, Schweiger M, Moschinger M, Xu H, Scherer T, Popa A, et al. CD8+ T cells induce cachexia during chronic viral infection. Nat Immunol. 2019;20(6):701–10. https://doi.org/10.1038/s41590-019-0397-y.
Bartley JM, Pan SJ, Keilich SR, Hopkins JW, Al-Naggar IM, Kuchel GA, et al. Aging augments the impact of influenza respiratory tract infection on mobility impairments, muscle-localized inflammation, and muscle atrophy. Aging (Albany NY). 2016;8(4):620. https://doi.org/10.18632/aging.100882.
Barton-Davis ER, Shoturma DI, Musaro A, Rosenthal N, Sweeney HL. Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. Proc Natl Acad Sci. 1998;95(26):15603–7. https://doi.org/10.1073/pnas.95.26.15603.
Brooks SV, Faulkner JA. Skeletal muscle weakness in old age: underlying mechanisms. Med Sci Sports Exerc. 1994;26(4):432–9.
Bruunsgaard H, Pedersen M, Pedersen BK. Aging and proinflammatory cytokines. Curr Opin Hematol. 2001;8(3):131–6. https://doi.org/10.1097/00062752-200105000-00001.
Ciciliot S, Rossi AC, Dyar KA, Blaauw B, Schiaffino S. Muscle type and fiber type specificity in muscle wasting. Int J Biochem Cell Biol. 2013;45(10):2191–9. https://doi.org/10.1016/j.biocel.2013.05.016.
Deng B, Wehling-Henricks M, Villalta SA, Wang Y, Tidball JG. IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration. J Immunol. 2012;189(7):3669–80. https://doi.org/10.4049/jimmunol.1103180.
Erben U, Loddenkemper C, Doerfel K, Spieckermann S, Haller D, Heimesaat MM, et al. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exp Pathol. 2014;7(8):4557–76.
Ferrucci L, Guralnik JM, Pahor M, Corti MC, Havlik RJ. Hospital diagnoses, Medicare charges, and nursing home admissions in the year when older persons become severely disabled. JAMA. 1997;277(9):728–34. https://doi.org/10.1001/jama.1997.03540330050034.
Frost RA, Lang CH. Skeletal muscle cytokines: regulation by pathogen-associated molecules and catabolic hormones. Curr Opin Clin Nutr Metab Care. 2005;8(3):255–63. https://doi.org/10.1097/01.mco.0000165003.16578.2d.
Gardner EM, Murasko DM. Age-related changes in type 1 and type 2 cytokine production in humans. In: Handbook of Immunosenescence: Basic Understanding and Clinical Implications; 2017. p. 1–34. https://doi.org/10.1023/a:1020151401826.
Gomez CR, Boehmer ED, Kovacs EJ. The aging innate immune system. Curr Opin Immunol. 2005;17(5):457–62. https://doi.org/10.1016/j.coi.2005.07.013.
Groom JR, Luster AD. CXCR3 in T cell function. Exp Cell Res. 2011;317(5):620–31. https://doi.org/10.1016/j.yexcr.2010.12.017.
Guttridge DC. Signaling pathways weigh in on decisions to make or break skeletal muscle. Curr Opin Clin Nutr Metab Care. 2004;7(4):443–50. https://doi.org/10.1097/01.mco.0000134364.61406.26.
Hawkley LC, Cacioppo JT. Stress and the aging immune system. Brain Behav Immun. 2004;18(2):114–9. https://doi.org/10.1016/j.bbi.2003.09.005.
Haynes L, Szaba FM, Eaton SM, Kummer LW, Lanthier PA, Petell AH, et al. Immunity to the conserved influenza nucleoprotein reduces susceptibility to secondary bacterial infections. J Immunol. 2012;189(10):4921–9. https://doi.org/10.4049/jimmunol.1201916.
Heron M. Deaths: leading causes for 2010. Natl Vital Statistics Rep. 2013;62(6):1–96 Hyattsville, MD: National Center for Health Statistics.
Horsley V, Jansen KM, Mills ST, Pavlath GK. IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell. 2003;113(4):483–94. https://doi.org/10.1016/s0092-8674(03)00319-2.
Jelley-Gibbs DM, Dibble JP, Brown DM, Strutt TM, McKinstry KK, Swain SL. Persistent depots of influenza antigen fail to induce a cytotoxic CD8 T cell response. J Immunol. 2007;178(12):7563–70. https://doi.org/10.4049/jimmunol.178.12.7563.
Jin RM, Blair SJ, Warunek J, Heffner RR, Blader IJ, Wohlfert EA. Regulatory T cells promote myositis and muscle damage in Toxoplasma gondii infection. J Immunol (Baltimore, Md. : 1950). 2017;198(1):352–62. https://doi.org/10.4049/jimmunol.1600914.
Kaur K, Sullivan M, Wilson PC. Targeting B cell responses in universal influenza vaccine design. Trends Immunol. 2011;32(11):524–31. https://doi.org/10.1016/j.it.2011.08.007.
Keilich SR, Bartley JM, Haynes L. Diminished immune responses with aging predispose older adults to common and uncommon influenza complications. Cell Immunol. 2019:103992. https://doi.org/10.1016/j.cellimm.2019.103992.
Kuiken T, Taubenberger JK. Pathology of human influenza revisited. Vaccine. 2008;26:D59–66. https://doi.org/10.1016/j.vaccine.2008.07.025.
Kumar A, Parrillo JE, Kumar A. Clinical review: myocardial depression in sepsis and septic shock. Crit Care. 2002;6(6):500–8. https://doi.org/10.1186/cc1822.
LaMere MW, Lam H-T, Moquin A, Haynes L, Lund FE, Randall TD, et al. Contributions of antinucleoprotein IgG to heterosubtypic immunity against influenza virus. J Immunol. 2011a;186(7):4331–9. https://doi.org/10.4049/jimmunol.1003057.
LaMere MW, Moquin A, Lee FE-H, Misra RS, Blair PJ, Haynes L, et al. Regulation of antinucleoprotein IgG by systemic vaccination and its effect on influenza virus clearance. J Virol. 2011b;85(10):5027–35. https://doi.org/10.1128/JVI.00150-11.
Lauder SN, Jones E, Smart K, Bloom A, Williams AS, Hindley JP, et al. Interleukin-6 limits influenza-induced inflammation and protects against fatal lung pathology. Eur J Immunol. 2013;43(10):2613–25. https://doi.org/10.1002/eji.201243018.
Lefebvre JS, Lorenzo EC, Masters AR, Hopkins JW, Eaton SM, Smiley ST, et al. Vaccine efficacy and T helper cell differentiation change with aging. Oncotarget. 2016;7(23):33581. https://doi.org/10.18632/oncotarget.9254.
Makita N, Hizukuri Y, Yamashiro K, Murakawa M, Hayashi Y. IL-10 enhances the phenotype of M2 macrophages induced by IL-4 and confers the ability to increase eosinophil migration. Int Immunol. 2014;27(3):131–41. https://doi.org/10.1093/intimm/dxu090.
Mathers AR, Cuff CF. Role of interleukin-4 (IL-4) and IL-10 in serum immunoglobulin G antibody responses following mucosal or systemic reovirus infection. J Virol. 2004;78(7):3352–60. https://doi.org/10.1128/JVI.78.7.3352-3360.2004.
McConeghy KW, Lee Y, Zullo AR, Banerjee G, Daiello L, Dosa D, et al. Influenza illness and hip fracture hospitalizations in nursing home residents: are they related? J Gerontol Ser A. 2017;73(12):1638–42. https://doi.org/10.1093/gerona/glx200.
McElhaney JE, Zhou X, Talbot HK, Soethout E, Bleackley RC, Granville DJ, et al. The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines. Vaccine. 2012;30(12):2060–7. https://doi.org/10.1016/j.vaccine.2012.01.015.
Meador BM, Krzyszton CP, Johnson RW, Huey KA. Effects of IL-10 and age on IL-6, IL-1β, and TNF-α responses in mouse skeletal and cardiac muscle to an acute inflammatory insult. J Appl Physiol. 2008;104(4):991–7. https://doi.org/10.1152/japplphysiol.01079.2007.
Mikhak Z, Fleming CM, Medoff BD, Thomas SY, Tager AM, Campanella GS, et al. STAT1 in peripheral tissue differentially regulates homing of antigen-specific Th1 and Th2 cells. J Immunol. 2006;176(8):4959–67. https://doi.org/10.4049/jimmunol.176.8.4959.
Morley JE, Baumgartner RN. Cytokine-related aging process, vol. 59: Oxford University Press; 2004. p. M924–9. https://doi.org/10.1093/gerona/59.9.M924.
Nagaraju K, Raben N, Loeffler L, Parker T, Rochon PJ, Lee E, et al. Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies. Proc Natl Acad Sci. 2000;97(16):9209–14. https://doi.org/10.1073/pnas.97.16.9209.
Nilwik R, Snijders T, Leenders M, Groen BB, van Kranenburg J, Verdijk LB, et al. The decline in skeletal muscle mass with aging is mainly attributed to a reduction in type II muscle fiber size. Exp Gerontol. 2013;48(5):492–8. https://doi.org/10.1016/j.exger.2013.02.012.
Oslund KL, Zhou X, Lee B, Zhu L, Duong T, Shih R, et al. Synergistic up-regulation of CXCL10 by virus and IFN γ in human airway epithelial cells. PLoS One. 2014;9(7):e100978. https://doi.org/10.1371/journal.pone.0100978.
Pattison JS, Folk LC, Madsen RW, Childs TE, Spangenburg EE, Booth FW. Expression profiling identifies dysregulation of myosin heavy chains IIb and IIx during limb immobilization in the soleus muscles of old rats. J Physiol. 2003;553(2):357–68. https://doi.org/10.1113/jphysiol.2003.047233.
Prieto S, Grau JM. The geoepidemiology of autoimmune muscle disease. Autoimmun Rev. 2010;9(5):A330–4. https://doi.org/10.1016/j.autrev.2009.11.006.
Pummerer CL, Luze K, Grässl G, Bachmaier K, Offner F, Burrell SK, et al. Identification of cardiac myosin peptides capable of inducing autoimmune myocarditis in BALB/c mice. J Clin Invest. 1996;97(9):2057–62. https://doi.org/10.1172/JCI118642.
Rose NR, Herskowitz A, Neumann DA, Neu N. Autoimmune myocarditis: a paradigm of post-infection autoimmune disease. Immunol Today. 1988;9(4):117–20. https://doi.org/10.1016/0167-5699(88)91282-0.
Roth SM, Metter EJ, Ling S, Ferrucci L. Inflammatory factors in age-related muscle wasting. Curr Opin Rheumatol. 2006;18(6):625–30. https://doi.org/10.1097/01.bor.0000245722.10136.6d.
Sartorius CA, Lu BD, Acakpo-Satchivi L, Jacobsen RP, Byrnes WC, Leinwand LA. Myosin heavy chains IIa and IId are functionally distinct in the mouse. J Cell Biol. 1998;141(4):943–53. https://doi.org/10.1083/jcb.141.4.943.
Shanely RA, Zwetsloot KA, Childs TE, Lees SJ, Tsika RW, Booth FW. IGF-I activates the mouse type IIb myosin heavy chain gene. Am J Phys Cell Phys. 2009;297(4):C1019–27. https://doi.org/10.1152/ajpcell.00169.2009.
Suzuki T, Bless DM, Connor NP, Ford CN, Lee K, Inagi K. Age-related alterations in myosin heavy chain isoforms in rat intrinsic laryngeal muscles. Ann Otol Rhinol Laryngol. 2002;111(11):962–7. https://doi.org/10.1177/000348940211101102.
Suzuki S, Utsugisawa K, Yoshikawa H, Motomura M, Matsubara S, Yokoyama K, et al. Autoimmune targets of heart and skeletal muscles in myasthenia gravis. Arch Neurol. 2009;66(11):1334–8. https://doi.org/10.1001/archneurol.2009.229.
Thompson LV. Effects of age and training on skeletal muscle physiology and performance. Phys Ther. 1994;74(1):71–81. https://doi.org/10.1093/ptj/74.1.71.
Thompson L. Contractile properties and protein isoforms of single skeletal muscle fibers from 12-and 30-month-old Fischer 344 Brown Norway F1 hybrid rats. Aging Clin Exp Res. 1999;11(2):109–18. https://doi.org/10.1007/BF03399649.
Thompson LV. Skeletal muscle adaptations with age, inactivity, and therapeutic exercise. J Orthop Sports Phys Ther. 2002;32(2):44–57. https://doi.org/10.2519/jospt.2002.32.2.44.
Thompson LV. Age-related muscle dysfunction. Exp Gerontol. 2009;44(1–2):106–11. https://doi.org/10.1016/j.exger.2008.05.003.
White JP. Control of skeletal muscle cell growth and size through adhesion GPCRs: Adhesion G Protein-coupled Receptors, Springer; 2016. p. 299–308. https://doi.org/10.1007/978-3-319-41523-9_13.
White C. Measuring social and externality benefits of influenza vaccination. J Hum Resour: 1118-9893R1112. 2019. https://doi.org/10.3368/jhr.56.3.1118-9893R2.
Wright CR, Allsopp GL, Addinsall AB, McRae NL, Andrikopoulos S, Stupka N. A reduction in selenoprotein S amplifies the inflammatory profile of fast-twitch skeletal muscle in the mdx dystrophic mouse. Mediat Inflamm. 2017;2017:1–12. https://doi.org/10.1155/2017/7043429.
Wynn TA. Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol. 2015;15(5):271–82. https://doi.org/10.1038/nri3831.
Yang M-L, Wang C-T, Yang S-J, Leu C-H, Chen S-H, Wu C-L, et al. IL-6 ameliorates acute lung injury in influenza virus infection. Sci Rep. 2017;7:43829. https://doi.org/10.1038/srep43829.
Zou Y, Dong Y, Meng Q, Zhao Y, Li N. Incorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophy. Sci Rep. 2018;8(1):2781. https://doi.org/10.1038/s41598-018-21122-5.
Acknowledgments
This research was partially conducted while Jenna Bartley was a Glenn/AFAR Postdoctoral Fellow. The primary monoclonal antibodies for myosin heavy chain type I (BA-D5), IIA (SC-71), and IIB (BF-F3), developed by S. Schiaffino at the University of Padova, was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH, and maintained at The University of Iowa, Department of Biology, Iowa City, IA 52242. The authors would like to thank Sandra Jastrzebski and Darcy Ahern for their assistance with experimental assays and manuscript preparation.
Funding
This work was supported by the National Institutes of Health/National Institute on Aging grants AG021600 and AG060389 (to L.H.)
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SRK, ECL, JMB, and LH conceived and designed the experiments. SRK, ECL, AGH, and BLT carried out experiments. SRK and ECL analyzed data. SRK led data interpretation and manuscript preparation. JMB and LH supervised the project and assisted with data interpretation and acquisition of funding. All authors discussed the results and contributed to the final manuscript.
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All mice were cared for in accordance with the recommendations in the Guide for the Care and use of Laboratory Animals of the National Institutes of Health. All procedures were approved by the University of Connecticut Medical School IACUC, protocol number 100705.
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Online Resource 1
Experimental plan for the experiments described. The timeline for our experiments depicting when mice were vaccinated, infected, and sacrificed. Figure made with biorender.com (PNG 439 kb)
Online Resource 2
Vaccination to influenza reduced flu-induced functional decrements in voluntary locomotor activity, grip strength, and gait kinematics. Young and aged C57BL/6 mice were vaccinated with NP/Alum or PBS before being intranasally infected with 500 EID50 of PR8 influenza. Mice were acclimated to testing prior to infection and tested for functional performance at designated time points. A-G) Gait parameters were assessed utilizing DigiGait, a ventral plane videography treadmill system 7 days post infection (n = 8–15). G) Spontaneous voluntary activity was assessed via the open field test at 8 days post infection (n = 10–15/group). I) Grip strength was determined by using a grip strength meter at day 8 post infection (n = 10–15/group). Data analyzed via two-way ANOVA with Bonferroni post hoc corrections comparing to NoVax/NoFlu age-matched controls (* = p < 0.05), comparing to NoVax/Flu age-matched controls (# = p < 0.05), and comparing between ages within a condition (brackets = p < 0.05) (PNG 141 kb)
Online Resource 3
Vaccination preserves architecture and nuclear infiltration of young and aged skeletal muscle H&E’s. A) The H&E’s are representative for each group at each time point analyzed. Scale bars are 100 μm. B) Blindly scored H&E summaries across each timepoint (n = 3–5). C) Muscle cross-sectional area via immunofluorescent staining from uninfected (left), unvaccinated/infected (middle), and vaccinated/infected (right) 9 DPI young mice. Colors: ‘myosin heavy chain I (red), myosin heavy chain IIA (green), myosin heavy chain IIB (yellow), myosin heavy chain IIX (no stain), nuclei (cyan). Scale bars are 100 μm. Data analyzed via two-way ANOVA with Bonferroni post hoc corrections comparing to NoVax/NoFlu age-matched controls (* = p < 0.05), comparing to NoVax/Flu age-matched controls (# = p < 0.05) (PNG 945 kb)
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Keilich, S.R., Lorenzo, E.C., Torrance, B.L. et al. Vaccination mitigates influenza-induced muscular declines in aged mice. GeroScience 42, 1593–1608 (2020). https://doi.org/10.1007/s11357-020-00206-z
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DOI: https://doi.org/10.1007/s11357-020-00206-z