論文

査読有り 本文へのリンクあり 国際誌
2018年10月

Angiotensin-converting enzyme 2 deficiency accelerates and angiotensin 1-7 restores age-related muscle weakness in mice

Journal of Cachexia, Sarcopenia and Muscle
  • Hikari Takeshita
  • Koichi Yamamoto
  • Satoko Nozato
  • Masao Takeda
  • So ichiro Fukada
  • Tadakatsu Inagaki
  • Hirotsugu Tsuchimochi
  • Mikiyasu Shirai
  • Yoichi Nozato
  • Taku Fujimoto
  • Yuki Imaizumi
  • Serina Yokoyama
  • Motonori Nagasawa
  • Go Hamano
  • Kazuhiro Hongyo
  • Tatsuo Kawai
  • Hiroko Hanasaki-Yamamoto
  • Shuko Takeda
  • Toshimasa Takahashi
  • Hiroshi Akasaka
  • Norihisa Itoh
  • Yoichi Takami
  • Yasushi Takeya
  • Ken Sugimoto
  • Hironori Nakagami
  • Hiromi Rakugi
  • 全て表示

9
5
開始ページ
975
終了ページ
986
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1002/jcsm.12334

© 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 Background: A pharmacologic strategy for age-related muscle weakness is desired to improve mortality and disability in the elderly. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II into angiotensin 1-7, a peptide known to protect against acute and chronic skeletal muscle injury in rodents. Since physiological aging induces muscle weakness via mechanisms distinct from other muscle disorders, the role of ACE2-angiotensin 1-7 in age-related muscle weakness remains undetermined. Here, we investigated whether deletion of ACE2 alters the development of muscle weakness by aging and whether angiotensin 1-7 reverses muscle weakness in older mice. Methods: After periodic measurement of grip strength and running distance in male ACE2KO and wild-type mice until 24 months of age, we infused angiotensin 1-7 or vehicle for 4 weeks, and measured grip strength, and excised tissues. Tissues were also excised from younger (3-month-old) and middle-aged (15-month-old) mice. Microarray analysis of RNA was performed using tibialis anterior (TA) muscles from middle-aged mice, and some genes were further tested using RT-PCR. Results: Grip strength of ACE2KO mice was reduced at 6 months and was persistently lower than that of wild-type mice (p < 0.01 at 6, 12, 18, and 24-month-old). Running distance of ACE2KO mice was shorter than that of wild-type mice only at 24 months of age [371 ± 26 vs. 479 ± 24 (m), p < 0.01]. Angiotensin 1-7 improved grip strength in both types of older mice, with larger effects observed in ACE2KO mice (% increase, 3.8 ± 1.5 and 13.3 ± 3.1 in wild type and ACE2KO mice, respectively). Older, but not middle-aged ACE2KO mice had higher oxygen consumption assessed by a metabolic cage than age-matched wild-type mice. Angiotensin 1-7 infusion modestly increased oxygen consumption in older mice. There was no difference in a wheel-running activity or glucose tolerance between ACE2KO and wild-type mice and between mice with vehicle and angiotensin 1-7 infusion. Analysis of TA muscles revealed that p16INK4a, a senescence-associated gene, and central nuclei of myofibers increased in middle-aged, but not younger ACE2KO mice. p16INK4a and central nuclei increased in TA muscles of older wild-type mice, but the differences between ACE2KO and wild-type mice remained significant (p < 0.01). Angiotensin 1-7 did not alter the expression of p16INK4a or central nuclei in TA muscles of both types of mice. Muscle ACE2 expression of wild-type mice was the lowest at middle age (2.6 times lower than younger age, p < 0.05). Conclusions: Deletion of ACE2 induced the early manifestation of muscle weakness with signatures of muscle senescence. Angiotensin 1-7 improved muscle function in older mice, supporting future application of the peptide or its analogues in the treatment of muscle weakness in the elderly population.

リンク情報
DOI
https://doi.org/10.1002/jcsm.12334
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/30207087
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204583
Scopus
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85053416580&origin=inward 本文へのリンクあり
Scopus Citedby
https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=85053416580&origin=inward
ID情報
  • DOI : 10.1002/jcsm.12334
  • ISSN : 2190-5991
  • eISSN : 2190-6009
  • PubMed ID : 30207087
  • PubMed Central 記事ID : PMC6204583
  • SCOPUS ID : 85053416580

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