Involvement of Parkin-mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease-related sarcopenia.

Autor: Ito A; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Hashimoto M; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Tanihata J; Department of Cell Physiology, The Jikei University, Tokyo, Japan., Matsubayashi S; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Sasaki R; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Fujimoto S; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Kawamoto H; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Hosaka Y; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Ichikawa A; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Kadota T; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Fujita Y; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Takekoshi D; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Ito S; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Minagawa S; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Numata T; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Hara H; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Matsuoka T; Department of Orthopedic Surgery, The Jikei University, Tokyo, Japan., Udaka J; Department of Orthopedic Surgery, The Jikei University, Tokyo, Japan., Araya J; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan., Saito M; Department of Orthopedic Surgery, The Jikei University, Tokyo, Japan., Kuwano K; Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University, Tokyo, Japan.
Jazyk: angličtina
Zdroj: Journal of cachexia, sarcopenia and muscle [J Cachexia Sarcopenia Muscle] 2022 Jun; Vol. 13 (3), pp. 1864-1882. Date of Electronic Publication: 2022 Apr 03.
DOI: 10.1002/jcsm.12988
Abstrakt: 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.
(© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)
Databáze: MEDLINE
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