mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy

被引:57
作者
Ching, James K. [1 ]
Elizabeth, Sarita V. [1 ]
Ju, Jeong-Sun [1 ]
Lusk, Caleb [1 ]
Pittman, Sara K. [1 ]
Weihl, Conrad C. [1 ]
机构
[1] Washington Univ, Sch Med, Dept Neurol, Hope Ctr Neurol Dis, St Louis, MO 63110 USA
基金
美国国家卫生研究院;
关键词
VCP MUTATIONS; PAGET-DISEASE; MOUSE MODEL; AUTOPHAGY; MUSCLE; INHIBITOR; P97; DEGENERATION; DEGRADATION; ACTIVATION;
D O I
10.1093/hmg/dds524
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Autophagy is dysfunctional in many degenerative diseases including myopathies. Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM) associated with Paget's disease of the bone, fronto-temporal dementia and amyotrophic lateral sclerosis (IBMPFD/ALS). VCP is necessary for protein degradation via the proteasome and lysosome. IBMPFD/ALS mutations in VCP disrupt autophagosome and endosome maturation resulting in vacuolation, weakness and muscle atrophy. To understand the regulation of autophagy in VCP-IBM muscle, we examined the AKT/FOXO3 and mammalian target of rapamycin (mTOR) pathways. Basal Akt and FOXO3 phosphorylation was normal. In contrast, the phosphorylation of mTOR targets was decreased. Consistent with this, global protein translation was diminished and autophagosome biogenesis was increased in VCP-IBM muscle. Further mTORC1 inhibition with rapamycin hastened weakness, atrophy and vacuolation in VCP-IBM mice. This was accompanied by the accumulation of autophagic substrates such as p62, LC3II and ubiquitinated proteins. The decrease in mTOR signaling was partially rescued by insulin and to a lesser extent by amino acid (AA) stimulation in VCP-IBM muscle. Cells expressing catalytically inactive VCP or treated with a VCP inhibitor also failed to activate mTOR upon nutrient stimulation. Expression of a constitutively active Rheb enhanced mTOR activity and increased the fiber size in VCP-IBM mouse skeletal muscle. These studies suggest that VCP mutations may disrupt mTOR signaling and contribute to IBMPFD/ALS disease pathogenesis. Treatment of some autophagic disorders with mTOR inhibitors such as rapamycin may worsen disease.
引用
收藏
页码:1167 / 1179
页数:13
相关论文
共 47 条
[1]   UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1α turnover [J].
Alexandru, Gabriela ;
Graumann, Johannes ;
Smith, Geoffrey T. ;
Kolawa, Natalie J. ;
Fang, Ruihua ;
Deshaies, Raymond J. .
CELL, 2008, 134 (05) :804-816
[2]   VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease [J].
Badadani, Mallikarjun ;
Nalbandian, Angele ;
Watts, Giles D. ;
Vesa, Jouni ;
Kitazawa, Masashi ;
Su, Hailing ;
Tanaja, Jasmin ;
Dec, Eric ;
Wallace, Douglas C. ;
Mukherjee, Jogeshwar ;
Caiozzo, Vincent ;
Warman, Matthew ;
Kimonis, Virginia E. .
PLOS ONE, 2010, 5 (10)
[3]   Autophagy is increased in laminin α2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A [J].
Carmignac, Virginie ;
Svensson, Martina ;
Korner, Zandra ;
Elowsson, Linda ;
Matsumura, Cintia ;
Gawlik, Kinga I. ;
Allamand, Valerie ;
Durbeej, Madeleine .
HUMAN MOLECULAR GENETICS, 2011, 20 (24) :4891-4902
[4]   Temsirolimus Activates Autophagy and Ameliorates Cardiomyopathy Caused by Lamin A/C Gene Mutation [J].
Choi, Jason C. ;
Muchir, Antoine ;
Wu, Wei ;
Iwata, Shinichi ;
Homma, Shunichi ;
Morrow, John P. ;
Worman, Howard J. .
SCIENCE TRANSLATIONAL MEDICINE, 2012, 4 (144)
[5]   Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways [J].
Chou, Tsui-Fen ;
Brown, Steve J. ;
Minond, Dmitriy ;
Nordin, Brian E. ;
Li, Kelin ;
Jones, Amanda C. ;
Chase, Peter ;
Porubsky, Patrick R. ;
Stoltz, Brian M. ;
Schoenen, Frank J. ;
Patricelli, Matthew P. ;
Hodder, Peter ;
Rosen, Hugh ;
Deshaies, Raymond J. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (12) :4834-4839
[6]   Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone [J].
Custer, Sara K. ;
Neumann, Manuela ;
Lu, Hongbo ;
Wright, Alexander C. ;
Taylor, J. Paul .
HUMAN MOLECULAR GENETICS, 2010, 19 (09) :1741-1755
[7]   p62 Is a Key Regulator of Nutrient Sensing in the mTORC1 Pathway [J].
Duran, Angeles ;
Amanchy, Ramars ;
Linares, Juan F. ;
Joshi, Jayashree ;
Abu-Baker, Shadi ;
Porollo, Aleksey ;
Hansen, Malene ;
Moscat, Jorge ;
Diaz-Meco, Maria T. .
MOLECULAR CELL, 2011, 44 (01) :134-146
[8]   SQSTM1 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis [J].
Fecto, Faisal ;
Yan, Jianhua ;
Vemula, S. Pavan ;
Liu, Erdong ;
Yang, Yi ;
Chen, Wenjie ;
Zheng, Jian Guo ;
Shi, Yong ;
Siddique, Nailah ;
Arrat, Hasan ;
Donkervoort, Sandra ;
Ajroud-Driss, Senda ;
Sufit, Robert L. ;
Heller, Scott L. ;
Deng, Han-Xiang ;
Siddique, Teepu .
ARCHIVES OF NEUROLOGY, 2011, 68 (11) :1440-1446
[9]   The Late Endosome is Essential for mTORC1 Signaling [J].
Flinn, Rory J. ;
Yan, Ying ;
Goswami, Sumanta ;
Parker, Peter J. ;
Backer, Jonathan M. .
MOLECULAR BIOLOGY OF THE CELL, 2010, 21 (05) :833-841
[10]   Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease [J].
Fukuda, T ;
Ewan, L ;
Bauer, M ;
Mattaliano, RJ ;
Zaal, K ;
Ralston, E ;
Plotz, PH ;
Raben, N .
ANNALS OF NEUROLOGY, 2006, 59 (04) :700-708