TY - JOUR
T1 - Impaired phagocytic function in CX3CR1+ tissue-resident skeletal muscle macrophages prevents muscle recovery after influenza A virus-induced pneumonia in old mice
AU - Runyan, Constance E.
AU - Welch, Lynn C.
AU - Lecuona, Emilia
AU - Shigemura, Masahiko
AU - Amarelle, Luciano
AU - Abdala-Valencia, Hiam
AU - Joshi, Nikita
AU - Lu, Ziyan
AU - Nam, Kiwon
AU - Markov, Nikolay S.
AU - McQuattie-Pimentel, Alexandra C.
AU - Piseaux-Aillon, Raul
AU - Politanska, Yuliya
AU - Sichizya, Lango
AU - Watanabe, Satoshi
AU - Williams, Kinola J.N.
AU - Budinger, G. R.Scott
AU - Sznajder, Jacob I.
AU - Misharin, Alexander V.
N1 - Funding Information:
Northwestern University Flow Cytometry Facility, Center for Advanced Microscopy, and Pathology Core Facility are supported by NCI Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. This research was supported in part through the computational resources and staff contributions provided by the Genomics Computing Cluster (Genomic Nodes on Quest) which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg's Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology.
Funding Information:
Satoshi Watanabe is supported by MSD Life Science Foundation, Public Interest Incorporated Foundation, Japan, and David W. Cugell and Christina Enroth‐Cugell Fellowship Program at Northwestern University. GR Scott Budinger is supported by NIH grants ES013995, HL071643, and AG049665, and the Veterans Administration Grant BX000201. Jacob I Sznajder is supported by NIH grants HL147070, HL071643, and AG049665. Alexander V Misharin is supported by NIH grants HL135124, AG049665, and AI135964.
Publisher Copyright:
© 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Skeletal muscle dysfunction in survivors of pneumonia disproportionately affects older individuals in whom it causes substantial morbidity. We found that skeletal muscle recovery was impaired in old compared with young mice after influenza A virus-induced pneumonia. In young mice, recovery of muscle loss was associated with expansion of tissue-resident skeletal muscle macrophages and downregulation of MHC II expression, followed by a proliferation of muscle satellite cells. These findings were absent in old mice and in mice deficient in Cx3cr1. Transcriptomic profiling of tissue-resident skeletal muscle macrophages from old compared with young mice showed downregulation of pathways associated with phagocytosis and proteostasis, and persistent upregulation of inflammatory pathways. Consistently, skeletal muscle macrophages from old mice failed to downregulate MHCII expression during recovery from influenza A virus-induced pneumonia and showed impaired phagocytic function in vitro. Like old animals, mice deficient in the phagocytic receptor Mertk showed no macrophage expansion, MHCII downregulation, or satellite cell proliferation and failed to recover skeletal muscle function after influenza A pneumonia. Our data suggest that a loss of phagocytic function in a CX3CR1+ tissue-resident skeletal muscle macrophage population in old mice precludes satellite cell proliferation and recovery of skeletal muscle function after influenza A pneumonia.
AB - Skeletal muscle dysfunction in survivors of pneumonia disproportionately affects older individuals in whom it causes substantial morbidity. We found that skeletal muscle recovery was impaired in old compared with young mice after influenza A virus-induced pneumonia. In young mice, recovery of muscle loss was associated with expansion of tissue-resident skeletal muscle macrophages and downregulation of MHC II expression, followed by a proliferation of muscle satellite cells. These findings were absent in old mice and in mice deficient in Cx3cr1. Transcriptomic profiling of tissue-resident skeletal muscle macrophages from old compared with young mice showed downregulation of pathways associated with phagocytosis and proteostasis, and persistent upregulation of inflammatory pathways. Consistently, skeletal muscle macrophages from old mice failed to downregulate MHCII expression during recovery from influenza A virus-induced pneumonia and showed impaired phagocytic function in vitro. Like old animals, mice deficient in the phagocytic receptor Mertk showed no macrophage expansion, MHCII downregulation, or satellite cell proliferation and failed to recover skeletal muscle function after influenza A pneumonia. Our data suggest that a loss of phagocytic function in a CX3CR1+ tissue-resident skeletal muscle macrophage population in old mice precludes satellite cell proliferation and recovery of skeletal muscle function after influenza A pneumonia.
KW - influenza
KW - macrophages
KW - pneumonia
KW - skeletal muscle
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U2 - 10.1111/acel.13180
DO - 10.1111/acel.13180
M3 - Article
C2 - 32720752
AN - SCOPUS:85088569049
SN - 1474-9718
VL - 19
JO - Aging Cell
JF - Aging Cell
IS - 9
M1 - e13180
ER -