Proteasome dysfunction induces muscle growth defects and protein aggregation.
The ubiquitin-proteasome and autophagy-lysosome pathways are the two major routes of protein and organelle clearance. The role of the proteasome pathway in mammalian muscle has not been examined in vivo. In this study, we report that the muscle-specific deletion of a crucial proteasomal gene, Rpt3 (also known as Psmc4), resulted in profound muscle growth defects and a decrease in force production in mice. Specifically, developing muscles in conditional Rpt3-knockout animals showed dysregulated proteasomal activity. The autophagy pathway was upregulated, but the process of autophagosome formation was impaired. A microscopic analysis revealed the accumulation of basophilic inclusions and disorganization of the sarcomeres in young adult mice. Our results suggest that appropriate proteasomal activity is important for muscle growth and for maintaining myofiber integrity in collaboration with autophagy pathways. The deletion of a component of the proteasome complex contributed to myofiber degeneration and weakness in muscle disorders that are characterized by the accumulation of abnormal inclusions.
Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan Department of Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Yasuo
Y
Kitajima
Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Yoshitaka
Y
Tashiro
Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan naoki@med.tohoku.ac.jp aokim@med.tohoku.ac.jp.
Naoki
N
Suzuki
Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Hitoshi
H
Warita
Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Masaaki
M
Kato
Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Maki
M
Tateyama
Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Risa
R
Ando
Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Rumiko
R
Izumi
Niigata University, Department of Cellular Neurobiology Brain Research Institute, Niigata 951-8510, Japan.
Maya
M
Yamazaki
Niigata University, Department of Cellular Neurobiology Brain Research Institute, Niigata 951-8510, Japan.
Manabu
M
Abe
Niigata University, Department of Cellular Neurobiology Brain Research Institute, Niigata 951-8510, Japan.
Kenji
K
Sakimura
Department of Neurology, Wakayama Medical University Graduate School of Medicine, Wakayama 641-8510, Japan.
Hidefumi
H
Ito
Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Makoto
M
Urushitani
Department of Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Ryoichi
R
Nagatomi
Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Ryosuke
R
Takahashi
Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan naoki@med.tohoku.ac.jp aokim@med.tohoku.ac.jp.
Masashi
M
Aoki
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001696:Biomechanical Phenomena / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D016189:Dystrophin / Q000378:metabolism; D007150:Immunohistochemistry; D018345:Mice, Knockout; D024510:Muscle Development / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development* / Q000473:pathology*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D066329:Protein Aggregates / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; D016189:Dystrophin; D061988:Proteasome Inhibitors; D066329:Protein Aggregates; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
Autophagy; Muscle atrophy; Proteasome; Skeletal muscle