Involvement of Parkin‐mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease‐related sarcopenia
Abstract Background Sarcopenia is characterized by the loss of skeletal muscle mass and strength and is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) exposure, a major cause for COPD, induces mitochondrial damage, which has been im...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-06-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jcsm.12988 |
| _version_ | 1827070723285319680 |
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| author | Akihiko Ito Mitsuo Hashimoto Jun Tanihata Sachi Matsubayashi Ryoko Sasaki Shota Fujimoto Hironori Kawamoto Yusuke Hosaka Akihiro Ichikawa Tsukasa Kadota Yu Fujita Daisuke Takekoshi Sabro Ito Shunsuke Minagawa Takanori Numata Hiromichi Hara Tatsuki Matsuoka Jun Udaka Jun Araya Mitsuru Saito Kazuyoshi Kuwano |
| author_facet | Akihiko Ito Mitsuo Hashimoto Jun Tanihata Sachi Matsubayashi Ryoko Sasaki Shota Fujimoto Hironori Kawamoto Yusuke Hosaka Akihiro Ichikawa Tsukasa Kadota Yu Fujita Daisuke Takekoshi Sabro Ito Shunsuke Minagawa Takanori Numata Hiromichi Hara Tatsuki Matsuoka Jun Udaka Jun Araya Mitsuru Saito Kazuyoshi Kuwano |
| author_sort | Akihiko Ito |
| collection | DOAJ |
| description | Abstract Background Sarcopenia is characterized by the loss of skeletal muscle mass and strength and is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) exposure, a major cause for COPD, induces mitochondrial damage, which has been implicated in sarcopenia pathogenesis. The current study sought to examine the involvement of insufficient Parkin‐mediated mitophagy, a mitochondrion‐selective autophagy, in the mechanisms by which dysfunctional mitochondria accumulate with excessive reactive oxygen species (ROS) production in the development of COPD‐related sarcopenia. Methods The involvement of Parkin‐mediated mitophagy was examined using in vitro models of myotube formation, in vivo CS‐exposure model using Parkin−/− mice, and human muscle samples from patients with COPD‐related sarcopenia. Results Cigarette smoke extract (CSE) induced myotube atrophy with concomitant 30% reduction in Parkin expression levels (P < 0.05). Parkin‐mediated mitophagy regulated myotube atrophy by modulating mitochondrial damage and mitochondrial ROS production. Increased mitochondrial ROS was responsible for myotube atrophy by activating Muscle Ring Finger 1 (MuRF‐1)‐mediated myosin heavy chain (MHC) degradation. Parkin−/− mice with prolonged CS exposure showed enhanced limb muscle atrophy with a 31.7% reduction in limb muscle weights (P < 0.01) and 2.3 times greater MuRF‐1 expression (P < 0.01) compared with wild‐type mice with concomitant accumulation of damaged mitochondria and oxidative modifications in 4HNE expression. Patients with COPD‐related sarcopenia exhibited significantly reduced Parkin but increased MuRF‐1 protein levels (35% lower and 2.5 times greater protein levels compared with control patients, P < 0.01 and P < 0.05, respectively) and damaged mitochondria accumulation demonstrated in muscles. Electric pulse stimulation‐induced muscle contraction prevented CSE‐induced MHC reduction by maintaining Parkin levels in myotubes. Conclusions Taken together, COPD‐related sarcopenia can be attributed to insufficient Parkin‐mediated mitophagy and increased mitochondrial ROS causing enhanced muscle atrophy through MuRF‐1 activation, which may be at least partly preventable through optimal physical exercise. |
| first_indexed | 2024-04-24T08:20:39Z |
| format | Article |
| id | doaj.art-ad895a5d387e4cd6855dea08a616154a |
| institution | Directory Open Access Journal |
| issn | 2190-5991 2190-6009 |
| language | English |
| last_indexed | 2025-03-20T00:27:03Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
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| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj.art-ad895a5d387e4cd6855dea08a616154a2024-10-10T03:50:48ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092022-06-011331864188210.1002/jcsm.12988Involvement of Parkin‐mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease‐related sarcopeniaAkihiko Ito0Mitsuo Hashimoto1Jun Tanihata2Sachi Matsubayashi3Ryoko Sasaki4Shota Fujimoto5Hironori Kawamoto6Yusuke Hosaka7Akihiro Ichikawa8Tsukasa Kadota9Yu Fujita10Daisuke Takekoshi11Sabro Ito12Shunsuke Minagawa13Takanori Numata14Hiromichi Hara15Tatsuki Matsuoka16Jun Udaka17Jun Araya18Mitsuru Saito19Kazuyoshi Kuwano20Division of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDepartment of Cell Physiology The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDepartment of Orthopedic Surgery The Jikei University Tokyo JapanDepartment of Orthopedic Surgery The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanDepartment of Orthopedic Surgery The Jikei University Tokyo JapanDivision of Respiratory Diseases, Department of Internal Medicine The Jikei University Tokyo JapanAbstract Background Sarcopenia is characterized by the loss of skeletal muscle mass and strength and is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) exposure, a major cause for COPD, induces mitochondrial damage, which has been implicated in sarcopenia pathogenesis. The current study sought to examine the involvement of insufficient Parkin‐mediated mitophagy, a mitochondrion‐selective autophagy, in the mechanisms by which dysfunctional mitochondria accumulate with excessive reactive oxygen species (ROS) production in the development of COPD‐related sarcopenia. Methods The involvement of Parkin‐mediated mitophagy was examined using in vitro models of myotube formation, in vivo CS‐exposure model using Parkin−/− mice, and human muscle samples from patients with COPD‐related sarcopenia. Results Cigarette smoke extract (CSE) induced myotube atrophy with concomitant 30% reduction in Parkin expression levels (P < 0.05). Parkin‐mediated mitophagy regulated myotube atrophy by modulating mitochondrial damage and mitochondrial ROS production. Increased mitochondrial ROS was responsible for myotube atrophy by activating Muscle Ring Finger 1 (MuRF‐1)‐mediated myosin heavy chain (MHC) degradation. Parkin−/− mice with prolonged CS exposure showed enhanced limb muscle atrophy with a 31.7% reduction in limb muscle weights (P < 0.01) and 2.3 times greater MuRF‐1 expression (P < 0.01) compared with wild‐type mice with concomitant accumulation of damaged mitochondria and oxidative modifications in 4HNE expression. Patients with COPD‐related sarcopenia exhibited significantly reduced Parkin but increased MuRF‐1 protein levels (35% lower and 2.5 times greater protein levels compared with control patients, P < 0.01 and P < 0.05, respectively) and damaged mitochondria accumulation demonstrated in muscles. Electric pulse stimulation‐induced muscle contraction prevented CSE‐induced MHC reduction by maintaining Parkin levels in myotubes. Conclusions Taken together, COPD‐related sarcopenia can be attributed to insufficient Parkin‐mediated mitophagy and increased mitochondrial ROS causing enhanced muscle atrophy through MuRF‐1 activation, which may be at least partly preventable through optimal physical exercise.https://doi.org/10.1002/jcsm.12988COPDParkinMuscle atrophyCigarette smokeMuscle contraction |
| spellingShingle | Akihiko Ito Mitsuo Hashimoto Jun Tanihata Sachi Matsubayashi Ryoko Sasaki Shota Fujimoto Hironori Kawamoto Yusuke Hosaka Akihiro Ichikawa Tsukasa Kadota Yu Fujita Daisuke Takekoshi Sabro Ito Shunsuke Minagawa Takanori Numata Hiromichi Hara Tatsuki Matsuoka Jun Udaka Jun Araya Mitsuru Saito Kazuyoshi Kuwano Involvement of Parkin‐mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease‐related sarcopenia Journal of Cachexia, Sarcopenia and Muscle COPD Parkin Muscle atrophy Cigarette smoke Muscle contraction |
| title | Involvement of Parkin‐mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease‐related sarcopenia |
| title_full | Involvement of Parkin‐mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease‐related sarcopenia |
| title_fullStr | Involvement of Parkin‐mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease‐related sarcopenia |
| title_full_unstemmed | Involvement of Parkin‐mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease‐related sarcopenia |
| title_short | Involvement of Parkin‐mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease‐related sarcopenia |
| title_sort | involvement of parkin mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease related sarcopenia |
| topic | COPD Parkin Muscle atrophy Cigarette smoke Muscle contraction |
| url | https://doi.org/10.1002/jcsm.12988 |
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