Abstract
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.
Highlights
While elderly individuals are at increased risk of developing and dying from pneumonia, most patients with access to modern health care survive (Jain et al, 2015; Thannickal et al, 2015)
Using reporter mice in which GFP is knocked into the Cx3cr1 gene (Cx3cr1GFP/+), we found that approximately 25-30% of skeletal muscle macrophages expressed Cx3cr1 in naïve mice (Figure S5), and both CX3CR1+ and CX3CR1- macrophages included populations that were MHCIIhigh and MHCIIlow (Figure 4H)
In young mice recovering from influenza A pneumonia, we observed expansion and downregulation of MHCII in skeletal muscle macrophages followed by muscle satellite cell proliferation
Summary
While elderly individuals are at increased risk of developing and dying from pneumonia, most patients with access to modern health care survive (Jain et al, 2015; Thannickal et al, 2015). A growing body of literature suggests that elderly pneumonia survivors are at increased risk of developing age-related disorders including persistent lung dysfunction (Mittl et al, 1994), skeletal muscle atrophy limiting mobility (Herridge et al, 2003), myocardial infarction (Corrales-Medina Vicente et al, 2012) chronic kidney disease (Murugan et al, 2010), dementia (Tate et al, 2014) and cognitive impairment (Girard et al, 2018). Persistent skeletal muscle weakness in survivors of severe pneumonia disproportionately affects elderly patients, resulting in reduced quality of life including an increased risk of hospitalizations, long-term disability, and loss of independence (Barreiro et al, 2015; Falsey et al, 2005; Gozalo et al, 2012; Herridge et al, 2011; Pfoh et al, 2016). The process of muscle repair has been studied in models of direct injury, for example freezing, trauma, and toxin injection, but the mechanisms by which muscle fibers are regenerated after the indirect injury that develops after pneumonia are not known
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