TY - JOUR
T1 - Aspiration pneumonia induces muscle atrophy in the respiratory, skeletal, and swallowing systems
AU - Komatsu, Riyo
AU - Okazaki, Tatsuma
AU - Ebihara, Satoru
AU - Kobayashi, Makoto
AU - Tsukita, Yoko
AU - Nihei, Mayumi
AU - Sugiura, Hisatoshi
AU - Niu, Kaijun
AU - Ebihara, Takae
AU - Ichinose, Masakazu
N1 - Funding Information:
We thank Brent Bell for reading the manuscript. The authors certify that they comply with the ethical guidelines for authorship and publishing of the Journal of Cachexia, Sarcopenia and Muscle.48 This manuscript has not been published previously or considered for publication concurrently in another publication. This study was supported by a Grant-In-Aid for Scientific Research from the Ministry of Education, Science and Culture of the Japanese Government to T.O. (no. 23890018 and no. 26461176), S.E. (no. 26460899, 15K11644, 15K12588, 15K01420, and 15K15254), and M.K. (no. 25860633), and by a grant from Novartis Foundation for Gerontological Research to T.O. Research Funding for Longevity Sciences (28-13) from the National Center for Geriatrics and Gerontology, and Research Promotion Grant from Toho University Graduate School of Medicine (no.17-04) to S.E. This research was supported by AMED (under grant number 17dk0110024) to T.E. and T.O.
Publisher Copyright:
© 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders
PY - 2018/8
Y1 - 2018/8
N2 - Background: Repetition of the onset of aspiration pneumonia in aged patients is common and causes chronic inflammation. The inflammation induces proinflammatory cytokine production and atrophy in the muscles. The proinflammatory cytokines induce muscle proteolysis by activating calpains and caspase-3, followed by further degradation by the ubiquitin-proteasome system. Autophagy is another pathway of muscle atrophy. However, little is known about the relationship between aspiration pneumonia and muscle. For swallowing muscles, it is not clear whether they produce cytokines. The main objective of this study was to determine whether aspiration pneumonia induces muscle atrophy in the respiratory (the diaphragm), skeletal (the tibialis anterior, TA), and swallowing (the tongue) systems, and their possible mechanisms. Methods: We employed a mouse aspiration pneumonia model and computed tomography (CT) scans of aged pneumonia patients. To induce aspiration pneumonia, mice were inoculated with low dose pepsin and lipopolysaccharide solution intra-nasally 5 days a week. The diaphragm, TA, and tongue were isolated, and total RNA, proteins, and frozen sections were stored. Quantitative real-time polymerase chain reaction determined the expression levels of proinflammatory cytokines, muscle E3 ubiquitin ligases, and autophagy related genes. Western blot analysis determined the activation of the muscle proteolysis pathway. Frozen sections determined the presence of muscle atrophy. CT scans were used to evaluate the muscle atrophy in aged aspiration pneumonia patients. Results: The aspiration challenge enhanced the expression levels of proinflammatory cytokines in the diaphragm, TA, and tongue. Among muscle proteolysis pathways, the aspiration challenge activated caspase-3 in all the three muscles examined, whereas calpains were activated in the diaphragm and the TA but not in the tongue. Activation of the ubiquitin-proteasome system was detected in all the three muscles examined. The aspiration challenge activated autophagy in the TA and the tongue, whereas weak or little activation was detected in the diaphragm. The aspiration challenge resulted in a greater proportion of smaller myofibers than in controls in the diaphragm, TA, and tongue, suggesting muscle atrophy. CT scans clearly showed that aspiration pneumonia was followed by muscle atrophy in aged patients. Conclusions: Aspiration pneumonia induced muscle atrophy in the respiratory, skeletal, and swallowing systems in a preclinical animal model and in human patients. Diaphragmatic atrophy may weaken the force of cough to expectorate sputum or mis-swallowed contents. Skeletal muscle atrophy may cause secondary sarcopenia. The atrophy of swallowing muscles may weaken the swallowing function. Thus, muscle atrophy could become a new therapeutic target of aspiration pneumonia.
AB - Background: Repetition of the onset of aspiration pneumonia in aged patients is common and causes chronic inflammation. The inflammation induces proinflammatory cytokine production and atrophy in the muscles. The proinflammatory cytokines induce muscle proteolysis by activating calpains and caspase-3, followed by further degradation by the ubiquitin-proteasome system. Autophagy is another pathway of muscle atrophy. However, little is known about the relationship between aspiration pneumonia and muscle. For swallowing muscles, it is not clear whether they produce cytokines. The main objective of this study was to determine whether aspiration pneumonia induces muscle atrophy in the respiratory (the diaphragm), skeletal (the tibialis anterior, TA), and swallowing (the tongue) systems, and their possible mechanisms. Methods: We employed a mouse aspiration pneumonia model and computed tomography (CT) scans of aged pneumonia patients. To induce aspiration pneumonia, mice were inoculated with low dose pepsin and lipopolysaccharide solution intra-nasally 5 days a week. The diaphragm, TA, and tongue were isolated, and total RNA, proteins, and frozen sections were stored. Quantitative real-time polymerase chain reaction determined the expression levels of proinflammatory cytokines, muscle E3 ubiquitin ligases, and autophagy related genes. Western blot analysis determined the activation of the muscle proteolysis pathway. Frozen sections determined the presence of muscle atrophy. CT scans were used to evaluate the muscle atrophy in aged aspiration pneumonia patients. Results: The aspiration challenge enhanced the expression levels of proinflammatory cytokines in the diaphragm, TA, and tongue. Among muscle proteolysis pathways, the aspiration challenge activated caspase-3 in all the three muscles examined, whereas calpains were activated in the diaphragm and the TA but not in the tongue. Activation of the ubiquitin-proteasome system was detected in all the three muscles examined. The aspiration challenge activated autophagy in the TA and the tongue, whereas weak or little activation was detected in the diaphragm. The aspiration challenge resulted in a greater proportion of smaller myofibers than in controls in the diaphragm, TA, and tongue, suggesting muscle atrophy. CT scans clearly showed that aspiration pneumonia was followed by muscle atrophy in aged patients. Conclusions: Aspiration pneumonia induced muscle atrophy in the respiratory, skeletal, and swallowing systems in a preclinical animal model and in human patients. Diaphragmatic atrophy may weaken the force of cough to expectorate sputum or mis-swallowed contents. Skeletal muscle atrophy may cause secondary sarcopenia. The atrophy of swallowing muscles may weaken the swallowing function. Thus, muscle atrophy could become a new therapeutic target of aspiration pneumonia.
KW - Aged patients
KW - Aspiration pneumonia
KW - Muscle atrophy
KW - Myokine
KW - Sarcopenia
UR - http://www.scopus.com/inward/record.url?scp=85052120268&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052120268&partnerID=8YFLogxK
U2 - 10.1002/jcsm.12297
DO - 10.1002/jcsm.12297
M3 - Article
C2 - 29790300
AN - SCOPUS:85052120268
VL - 9
SP - 643
EP - 653
JO - Journal of Cachexia, Sarcopenia and Muscle
JF - Journal of Cachexia, Sarcopenia and Muscle
SN - 2190-5991
IS - 4
ER -