TY - JOUR
T1 - Inducible Rpt3, a Proteasome Component, Knockout in Adult Skeletal Muscle Results in Muscle Atrophy
AU - Kitajima, Yasuo
AU - Suzuki, Naoki
AU - Yoshioka, Kiyoshi
AU - Izumi, Rumiko
AU - Tateyama, Maki
AU - Tashiro, Yoshitaka
AU - Takahashi, Ryosuke
AU - Aoki, Masashi
AU - Ono, Yusuke
N1 - Funding Information:
We thank Hinako Shigihara, Biomedical Research Core of Tohoku University Graduate School of Medicine for histological and electro-microscopic analysis. Funding. This work was supported by the Grant-in-Aid for Scientific Research KAKENHI (15H05667, 16H05318, 18H03193, 18K07519, 18K17857, and 20H04078). This work was also supported by the Suzuken Memorial Foundation, and AMED (16bm0704010h0001, 18dk0310086, 18ek0109383h0001, and 19bm0704036h0001).
Publisher Copyright:
© Copyright © 2020 Kitajima, Suzuki, Yoshioka, Izumi, Tateyama, Tashiro, Takahashi, Aoki and Ono.
PY - 2020/9/2
Y1 - 2020/9/2
N2 - The ubiquitin–proteasome system has the capacity to degrade polyubiquitinated proteins and plays an important role in many cellular processes. However, the role of Rpt3, a crucial proteasomal gene, has not been investigated in adult muscles in vivo. Herein, we generated skeletal-muscle-specific Rpt3 knockout mice, in which genetic inactivation of Rpt3 could be induced by doxycycline administration. The Rpt3-knockout mice showed a significant reduction by more than 90% in the expression of Rpt3 in adult muscles. Using this model, we found that proteasome dysfunction in adult muscles resulted in muscle wasting and a decrease in the myofiber size. Immunoblotting analysis showed that the amounts of ubiquitinated proteins were markedly higher in muscles of Rpt3-deficient mice than in those of the control mice. Analysis of the autophagy pathway in the Rpt3-deficient mice showed that the upregulation of LC3II, p62, Atg5, Atg7, and Beclin-1 in protein levels, which supposed to be compensatory proteolysis activation. Our results suggest that the proteasome inhibition in adult muscle severely deteriorates myofiber integrity and results in muscle atrophy.
AB - The ubiquitin–proteasome system has the capacity to degrade polyubiquitinated proteins and plays an important role in many cellular processes. However, the role of Rpt3, a crucial proteasomal gene, has not been investigated in adult muscles in vivo. Herein, we generated skeletal-muscle-specific Rpt3 knockout mice, in which genetic inactivation of Rpt3 could be induced by doxycycline administration. The Rpt3-knockout mice showed a significant reduction by more than 90% in the expression of Rpt3 in adult muscles. Using this model, we found that proteasome dysfunction in adult muscles resulted in muscle wasting and a decrease in the myofiber size. Immunoblotting analysis showed that the amounts of ubiquitinated proteins were markedly higher in muscles of Rpt3-deficient mice than in those of the control mice. Analysis of the autophagy pathway in the Rpt3-deficient mice showed that the upregulation of LC3II, p62, Atg5, Atg7, and Beclin-1 in protein levels, which supposed to be compensatory proteolysis activation. Our results suggest that the proteasome inhibition in adult muscle severely deteriorates myofiber integrity and results in muscle atrophy.
KW - Rpt3
KW - adult skeletal muscle
KW - muscle atrophy
KW - muscle homeostasis
KW - sarcopenia
KW - ubiquitin proteasome system
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U2 - 10.3389/fcell.2020.00859
DO - 10.3389/fcell.2020.00859
M3 - Article
AN - SCOPUS:85091025107
SN - 2296-634X
VL - 8
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
M1 - 859
ER -