Role of PI3K/AKT/mTOR Signaling Pathway in Skeletal Muscle Atrophy in COPD Rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LiYanli ,  HanFengfeng , LiYan , LiuQian , CuiZhilei , 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 diseases; Rats; Skeletal muscle; Atrophy; PI3K/AKT/mTOR signaling pathway

DOI：

10.7507/1671-6205.2014116

Video：

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Objective To investigate the role of PI3K/AKT/mTOR signaling pathway in skeletal muscle atrophy in rats with chronic obstructive pulmonary diseases(COPD). Methods Passive cigarette smoking was used to establish COPD model.The protein expression of PI3K, total mTOR, phosphorylated-mTOR, total GSK-3β, phosphorylated-GSK-3β, total 4E-BP1, phosphorylated-4E-BP1, total p70S6K1 and phosphorylated-p70S6K1 in extensor digitorum longus of rats were measured by Western blot. Results The protein expression of PI3K was not significantly different between two groups(P > 0.05).Compared with the control group, the protein expression of total mTOR, phosphorylated-mTOR, total GSK-3β, and phosphorylated-GSK-3βincreased significantly in the COPD group(P < 0.05).The protein expression of total 4E-BP1 and total p70S6K1 were not significantly different between two groups(P > 0.05).While the protein expression of phosphorylated-4E-BP1 and phosphorylated-p70S6K1 significantly increased in the COPD group(P < 0.05). Conclusion The protein expressions of PI3K/AKT/mTOR signaling pathway in extensor digitorum longus increased significantly in COPD rats, suggesting that the activity of PI3K/AKT/mTOR signaling pathway increased, which may be one of the compensatory mechanism of skeletal muscle atrophy in COPD.

Citation： LiYanli, HanFengfeng, LiYan, LiuQian, CuiZhilei, LuoYong, XuWeiguo. Role of PI3K/AKT/mTOR Signaling Pathway in Skeletal Muscle Atrophy in COPD Rats. Chinese Journal of Respiratory and Critical Care Medicine, 2014, 13(5): 474-479. doi: 10.7507/1671-6205.2014116 Copy

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2.	韩锋锋, 徐卫国, 崔志磊, 等.AKT/FOXOs/Atrogin-1/MuRF1信号通路在慢性阻塞性肺疾病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.
3.	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.
4.	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.中国呼吸与重症监护杂志, 2010, 9:141-144.
5.	Sandri M.Signaling in muscle atrophy and hypertrophy.Physiology (Bethesda), 2008, 23:160-170.
6.	Toker A, Cantley LC.Signalling through the lipid products of phosphoinositide-3-OH kinase.Nature, 1997, 387:673-676.
7.	Maehama T, Dixon JE.The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3, 4, 5-trisphosphate.J Biol Chem, 1998, 273:13375-13378.
8.	Hirai K, Hayashi T, Chan PH, et al.PI3K in hibition inneonatal rat brain slices during and after hypoxia reduces phospho-Akt and increases cytosolic cytochrome c and apoptosis.Brain Res Mol Brain Res, 2004, 124:51-61.
9.	Nojima H, Tokunaga C, Eguchi S, et al.The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif.J Biol Chem, 2003, 278:15461-15464.
10.	Vyas DR, Spangenburg EE, Abraha TW, et al.GSK-3βnegatively regulates skeletal myotube hypertrophy.Am J Physiol, 2002, 283:545-551.
11.	Altomare DA, Khaled AR.Homeostasis and the importance for a balance between AKT/mTOR activity and intracellular signaling.Curr Med Chem, 2012, 19:3748-3762.
12.	Fernandez-Twinn DS, Blackmore HL, Siggens L, et al.The programming of cardiac hypertrophy in the offspring by maternal obesity is associated with hyperinsulinemia, AKT, ERK, and mTOR activation.Endocrinology, 2012, 153:5961-5971.
13.	Surviladze Z, Sterk RT, DeHaro SA.Cellular entry of human papillomavirus type 16 involves activation of the phosphatidylinositol 3-Kinase/Akt/mTOR pathway and inhibition of autophagy.J Virol, 2013, 87:2508-2517.
14.	Liu Y, Cao GF, Xue J, et al.Tumor necrosis factor-alpha (TNF-α)-mediated in vitro human retinal pigment epithelial (RPE) cell migration mainly requires Akt/mTOR complex 1(mTORC1), but not mTOR complex 2(mTORC2) signaling.Eur J Cell Biol, 2012, 91:728-737.
15.	Carpenter RL, Jiang BH.Roles of EGFR, PI3K, AKT, and mTOR in heavy metal-induced cancer.Curr Cancer Drug Targets, 2013, 13:252-266.
16.	Gurpinar E, Grizzle WE, Shacka JJ, et al.A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagy.Mol Cancer Ther, 2013, 12:663-674.
17.	Yoshihara T, Naito H, Kakigi R, et al.Heat stress activates the Akt/mTOR signalling pathway in rat skeletal muscle.Acta Physiol, 2013, 207:416-426.
18.	Leger B, Cartoni R, Praz M, et al.Akt signalling through GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy.J Physiol, 2006, 576:923-933.
19.	Norrby M, Evertsson K, Fjällstr m AK, et al.Akt (protein kinase B) isoform phosphorylation and signaling downstream of mTOR (mammalian target of rapamycin) in denervated atrophic and hypertrophic mouse skeletal muscle.J Mol Signal, 2012, 7:7.
20.	Liu X, Joshi SK, Samagh SP, et al.Evaluation of Akt/mTOR Activity in muscle atrophy after rotator cuff tears in a rat model.J Orthop Res, 2012, 30:1440-1446.
21.	Plant PJ, Brooks D, Faughnan M, et al.Cellular markers of muscle atrophy in chronic obstructive pulmonary disease.Am J Respir Cell Mol Biol, 2010, 42:461-471.
22.	Lewis A, Riddoch-Contreras J, Natanek SA, et al.Downregulation of the serum response factor/miR-1 axis in the quadriceps of patients with COPD.Thorax, 2012, 67:26-34.
23.	Vogiatzis I, Simoes DC, Stratakos G, et al.Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD.Eur Respir J, 2010, 36:301-310.
24.	Wüst RC, Degens H.Factors contributing to muscle wasting and dysfunction in COPD patients.Int J Chron Obstruct Pulmon Dis, 2007, 2:289-300.
25.	Verhees KJ, Pansters NA, Schols AM, et al.Regulation of skeletal muscle plasticity by glycogen synthase kinase-3β:a potential target for the treatment of muscle wasting.Curr Pharm Des, 2013, 19:3276-3298.

1. 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.
2. 韩锋锋, 徐卫国, 崔志磊, 等.AKT/FOXOs/Atrogin-1/MuRF1信号通路在慢性阻塞性肺疾病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.
3. 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.
4. 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.中国呼吸与重症监护杂志, 2010, 9:141-144.
5. Sandri M.Signaling in muscle atrophy and hypertrophy.Physiology (Bethesda), 2008, 23:160-170.
6. Toker A, Cantley LC.Signalling through the lipid products of phosphoinositide-3-OH kinase.Nature, 1997, 387:673-676.
7. Maehama T, Dixon JE.The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3, 4, 5-trisphosphate.J Biol Chem, 1998, 273:13375-13378.
8. Hirai K, Hayashi T, Chan PH, et al.PI3K in hibition inneonatal rat brain slices during and after hypoxia reduces phospho-Akt and increases cytosolic cytochrome c and apoptosis.Brain Res Mol Brain Res, 2004, 124:51-61.
9. Nojima H, Tokunaga C, Eguchi S, et al.The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif.J Biol Chem, 2003, 278:15461-15464.
10. Vyas DR, Spangenburg EE, Abraha TW, et al.GSK-3βnegatively regulates skeletal myotube hypertrophy.Am J Physiol, 2002, 283:545-551.
11. Altomare DA, Khaled AR.Homeostasis and the importance for a balance between AKT/mTOR activity and intracellular signaling.Curr Med Chem, 2012, 19:3748-3762.
12. Fernandez-Twinn DS, Blackmore HL, Siggens L, et al.The programming of cardiac hypertrophy in the offspring by maternal obesity is associated with hyperinsulinemia, AKT, ERK, and mTOR activation.Endocrinology, 2012, 153:5961-5971.
13. Surviladze Z, Sterk RT, DeHaro SA.Cellular entry of human papillomavirus type 16 involves activation of the phosphatidylinositol 3-Kinase/Akt/mTOR pathway and inhibition of autophagy.J Virol, 2013, 87:2508-2517.
14. Liu Y, Cao GF, Xue J, et al.Tumor necrosis factor-alpha (TNF-α)-mediated in vitro human retinal pigment epithelial (RPE) cell migration mainly requires Akt/mTOR complex 1(mTORC1), but not mTOR complex 2(mTORC2) signaling.Eur J Cell Biol, 2012, 91:728-737.
15. Carpenter RL, Jiang BH.Roles of EGFR, PI3K, AKT, and mTOR in heavy metal-induced cancer.Curr Cancer Drug Targets, 2013, 13:252-266.
16. Gurpinar E, Grizzle WE, Shacka JJ, et al.A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagy.Mol Cancer Ther, 2013, 12:663-674.
17. Yoshihara T, Naito H, Kakigi R, et al.Heat stress activates the Akt/mTOR signalling pathway in rat skeletal muscle.Acta Physiol, 2013, 207:416-426.
18. Leger B, Cartoni R, Praz M, et al.Akt signalling through GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy.J Physiol, 2006, 576:923-933.
19. Norrby M, Evertsson K, Fjällstr m AK, et al.Akt (protein kinase B) isoform phosphorylation and signaling downstream of mTOR (mammalian target of rapamycin) in denervated atrophic and hypertrophic mouse skeletal muscle.J Mol Signal, 2012, 7:7.
20. Liu X, Joshi SK, Samagh SP, et al.Evaluation of Akt/mTOR Activity in muscle atrophy after rotator cuff tears in a rat model.J Orthop Res, 2012, 30:1440-1446.
21. Plant PJ, Brooks D, Faughnan M, et al.Cellular markers of muscle atrophy in chronic obstructive pulmonary disease.Am J Respir Cell Mol Biol, 2010, 42:461-471.
22. Lewis A, Riddoch-Contreras J, Natanek SA, et al.Downregulation of the serum response factor/miR-1 axis in the quadriceps of patients with COPD.Thorax, 2012, 67:26-34.
23. Vogiatzis I, Simoes DC, Stratakos G, et al.Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD.Eur Respir J, 2010, 36:301-310.
24. Wüst RC, Degens H.Factors contributing to muscle wasting and dysfunction in COPD patients.Int J Chron Obstruct Pulmon Dis, 2007, 2:289-300.
25. Verhees KJ, Pansters NA, Schols AM, et al.Regulation of skeletal muscle plasticity by glycogen synthase kinase-3β:a potential target for the treatment of muscle wasting.Curr Pharm Des, 2013, 19:3276-3298.

Chinese Journal of Respiratory and Critical Care Medicine

Role of PI3K/AKT/mTOR Signaling Pathway in Skeletal Muscle Atrophy in COPD Rats

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