Role of Autophagy-lysosomal System in Skeletal Muscle Atrophy in COPD Rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LiYan ,  HanFengfeng , LiYanli , YuHaiyang , LuoYong , XuWeiguo

Departmant of Respiratory Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China;

Corresponding author：

HanFengfeng, Email: fengfh86@sina.com

Keywords：

Chronic obstructive pulmonary disease; Rats; Skeletal muscle; Atrophy; Autophagy-lysosomal system

DOI：

10.7507/1671-6205.2015132

Video：

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Objective To investigate the role of autophagy-lysosomal system in skeletal muscle atrophy in rats with chronic obstructive pulmonary disease (COPD). Methods Passive cigarette smoking was used to establish COPD model. The mRNA and protein expression of FOXO transcription factor and autophagy-related genes Bnip3, Beclin1, p62, MAP-LC3Ⅱ/Ⅰ, Atg5 in extensor digitorum longus of rats were measured by real time PCR and Western blot. The changes of extensor digitorum longus tissue sections and lung tissue sections in the experimental group rats were observed under transmission electron microscopy. Results Compared with the control group, the mRNA expression of FOXO transcription factor and autophagy-related genes Bnip3, Beclin1, p62, Atg5 in extensor digitorum longus of the experimental group group rats was significantly increased (all P<0.05, as for Bnip3, the P value between two groups <0.01); The mRNA expression of MAP-LC3Ⅱ/Ⅰwas not significantly different between two groups (P>0.05). The protein expression of FOXO, Bnip3, Beclin1, p62, MAP-LC3Ⅱ/Ⅰ, Atg5 significantly increased in the COPD group (all P<0.05, as for Bnip3, MAP-LC3Ⅱ/Ⅰ, Beclin1, the P values between two groups <0.01). Compared with the control group, autolysosome in extensor digitorum longus tissue sections of the experimental group rats increased and lung tissue fibrosis and more inflammatory cells were observed in lung tissue sections of the experimental group rats under transmission electron microscopy. Conclusion The mRNA and protein expressions of FOXO transcription factor and autophagy-related genes in extensor digitorum longus increase significantly in the experimental group rats, suggesting that the activity of autophagy-lysosomal system, which may be one mechanism of skeletal muscle atrophy in COPD.

Citation： LiYan, HanFengfeng, LiYanli, YuHaiyang, LuoYong, XuWeiguo. Role of Autophagy-lysosomal System in Skeletal Muscle Atrophy in COPD Rats. Chinese Journal of Respiratory and Critical Care Medicine, 2015, 14(6): 534-540. doi: 10.7507/1671-6205.2015132 Copy

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13.	Ottenheijm CA, Heunks LM, Li YP, et al. Activation of the ubiquitin-proteasome pathway in the diaphragm in chronic obstructive pulmonary disease. Am J Respir Crit Care Med,2006,174:997-1002.
14.	韩锋锋,罗勇,徐卫国.慢性阻塞性肺疾病大鼠骨骼肌组织泛素系统基因及蛋白表达变化的研究.上海医学,2008,31:571-574.
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24.	Hussain SN, Mofarrahi M, Sigala I, et al. Mechanical ventilation-induced diaphragm disuse in humans triggers autophagy. Am J Respir Crit Care Med,2010,182:1377-1386.
25.	Carmignac V, Svensson M, Körner Z, et al. Autophagy is increased in laminin α2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A. Hum Mol Genet,2011,20:4891-4902.
26.	Dobrowolny G, Aucello M, Rizzuto E, et al. Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab,2008,8:425-436.
27.	She P, Zhang Z, Marchionini D, et al. Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington's disease. Am J Physiol Endocrinol Metab,2011,301:E49-E61.
28.	Pankiv S, Clausen TH, Lamark T, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem,2007,282:24131-24145.
29.	Tassa A, Roux MP, Attaix D, et al. Class Ⅲ phosphoinositide 3-kinase--Beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes. Biochem J,2003,376:577-586.
30.	徐俊,黄秀兰.SIRT1-FoxO-自噬通路研究进展.中国药理学通报,2014,30:901-904.
31.	Piétri-Rouxel F, Gentil C, Vassilopoulos S, et al. DHPR alpha1S subunit controls skeletal muscle mass and morphogenesis. EMBO J,2010,29:643-654.
32.	Chen ZH, Kim HP, Sciurba FC, et al. Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS One,2008,3:e3316.
33.	Chen ZH, Lam HC, Jin Y, et al. Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. Proc Natl Acad Sci USA,2010,107:18880-18885.
34.	Clague MJ, Urbe S. Ubiquitin:same molecule, different degradation pathways. Cell,2010,143:682-685.
35.	Nedelsky NB, Todd PK, Taylor JP. Autophagy and the ubiquitin-proteasome system:collaborators in neuroprotection. Biochim Biophys Acta,2008,1782:691-699.

1. Burtin C, Decramer M, Gosselink R, et al. Rehabilitation and acute exacerbations. Eur Respir J,2011,38:702-712.
2. Macklem PT. Therapeutic implications of the pathophysiology of COPD. Eur Respir J,2010,35:676-680.
3. Barnes PJ, Celli BR.Systemic manifestations and comorbidities of COPD. Eur Respir J,2009,33:1165-1185.
4. Debigaré R, Marquis K, Côté CH, et al. Catabolic/anabolic balance and muscle wasting in patients with COPD. Chest,2003,124:83-89.
5. 杨天芸,徐卫国,罗勇,等.慢性阻塞性肺病大鼠骨骼肌蛋白降解的变化.上海交通大学学报(医学版),2008,26:525-531.
6. 韩锋锋,徐卫国,崔志磊,等.AKT/FOXOs/atrogin-1/MuRF1信号通路在COPD大鼠骨骼肌萎缩中的作用.中国呼吸与危重监护杂志,2013,12:217-222.
7. 杨天芸,罗勇,徐卫国.慢性阻塞性肺病大鼠骨骼肌肌纤维类型和运动终板的变化.中国全科医学,2008,11:467-469.
8. Raguso CA, Luthy C. Nutritional status in chronic obstructive pulmonary disease:role of hypoxia. Nutrition,2011,27:138-143.
9. Kim HC, Mofarrahi M, Hussain SN. Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis,2008,3:637-658.
10. Sandri M. Signaling in muscle atrophy and hypertrophy. Physiology (Bethesda),2008,23:160-170.
11. Taillandier D, Combaret L, Pouch MN, et al. The role of ubiquitin-proteasome-dependent proteolysis in the remodelling of skeletal muscle. Proc Nutr Soc,2004,63:357-361.
12. McKinnell IW, Rudnicki MA. Molecular mechanisms of muscle atrophy. Cell,2004,119:907-910.
13. Ottenheijm CA, Heunks LM, Li YP, et al. Activation of the ubiquitin-proteasome pathway in the diaphragm in chronic obstructive pulmonary disease. Am J Respir Crit Care Med,2006,174:997-1002.
14. 韩锋锋,罗勇,徐卫国.慢性阻塞性肺疾病大鼠骨骼肌组织泛素系统基因及蛋白表达变化的研究.上海医学,2008,31:571-574.
15. 韩锋锋,徐卫国,罗勇,等.COPD大鼠膈肌组织泛素-蛋白酶体途径的研究.中国呼吸与危重监护杂志,2010,9:141-144.
16. 韩锋锋,罗勇,杨天芸,等.COPD大鼠骨骼肌组织20s蛋白酶体C2亚基的基因及蛋白表达变化的研究.中国全科医学,2010,13:3289-3292.
17. Doucet M, Dubé A, Joanisse DR, et al. Atrophy and hypertrophy signalling of the quadriceps and diaphragm in COPD. Thorax,2010,65:963-970.
18. Testelmans D, Crul T, Maes K, et al. Atrophy and hypertrophy signaling in the diaphragm of patients with COPD. Eur Respir J,2010,35:549-556.
19. Rubinsztein DC, Mariño G, Kroemer G. Autophagy and aging. Cell,2011,146:682-695.
20. 黄娟,袁伟杰.骼肌萎缩中的自噬现象及在慢性肾脏病中的研究前景.中国医学杂志,2013,93:1758-1760.
21. Lecker SH, Jagoe RT, Gilbert A, et al. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J,2004,18:39-51.
22. Mammucari C, Milan G, Romanello V, et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab,2007,6:458-471.
23. Zhao J, Brauh JJ, Sehiht A, et al. FoxO3 coordinately activates Protein degradation by the autophgic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab,2007,6:472-483.
24. Hussain SN, Mofarrahi M, Sigala I, et al. Mechanical ventilation-induced diaphragm disuse in humans triggers autophagy. Am J Respir Crit Care Med,2010,182:1377-1386.
25. Carmignac V, Svensson M, Körner Z, et al. Autophagy is increased in laminin α2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A. Hum Mol Genet,2011,20:4891-4902.
26. Dobrowolny G, Aucello M, Rizzuto E, et al. Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab,2008,8:425-436.
27. She P, Zhang Z, Marchionini D, et al. Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington's disease. Am J Physiol Endocrinol Metab,2011,301:E49-E61.
28. Pankiv S, Clausen TH, Lamark T, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem,2007,282:24131-24145.
29. Tassa A, Roux MP, Attaix D, et al. Class Ⅲ phosphoinositide 3-kinase--Beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes. Biochem J,2003,376:577-586.
30. 徐俊,黄秀兰.SIRT1-FoxO-自噬通路研究进展.中国药理学通报,2014,30:901-904.
31. Piétri-Rouxel F, Gentil C, Vassilopoulos S, et al. DHPR alpha1S subunit controls skeletal muscle mass and morphogenesis. EMBO J,2010,29:643-654.
32. Chen ZH, Kim HP, Sciurba FC, et al. Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS One,2008,3:e3316.
33. Chen ZH, Lam HC, Jin Y, et al. Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. Proc Natl Acad Sci USA,2010,107:18880-18885.
34. Clague MJ, Urbe S. Ubiquitin:same molecule, different degradation pathways. Cell,2010,143:682-685.
35. Nedelsky NB, Todd PK, Taylor JP. Autophagy and the ubiquitin-proteasome system:collaborators in neuroprotection. Biochim Biophys Acta,2008,1782:691-699.

Chinese Journal of Respiratory and Critical Care Medicine

Role of Autophagy-lysosomal System in Skeletal Muscle Atrophy in COPD Rats

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