Genetic Deletion of TrkB.T1 Increases Neuromuscular Function

Overview

Journal Am J Physiol Cell Physiol

Publisher American Physiological Society

Specialties Cell Biology
Physiology

Date 2011 Aug 26

PMID 21865582

Citations 28

Authors

Susan G Dorsey

Richard M Lovering

Cynthia L Renn

Carmen C Leitch

Xinyue Liu

Luke J Tallon

Lisa DeShong Sadzewicz

Abhishek Pratap

Sandra Ott

Naomi Sengamalay

Kristie M Jones

Colleen Barrick

Gianluca Fulgenzi

Jodi Becker

Kevin Voelker

Robert Talmadge

Brandon K Harvey

Ryan M Wyatt

Elizabeth Vernon-Pitts

Chao Zhang

Kevan Shokat

Claire Fraser-Liggett

Rita J Balice-Gordon

Lino Tessarollo

Christopher W Ward

Affiliations

Soon will be listed here.

Abstract

Neurotrophin-dependent activation of the tyrosine kinase receptor trkB.FL modulates neuromuscular synapse maintenance and function; however, it is unclear what role the alternative splice variant, truncated trkB (trkB.T1), may have in the peripheral neuromuscular axis. We examined this question in trkB.T1 null mice and demonstrate that in vivo neuromuscular performance and nerve-evoked muscle tension are significantly increased. In vitro assays indicated that the gain-in-function in trkB.T1(-/-) animals resulted specifically from an increased muscle contractility, and increased electrically evoked calcium release. In the trkB.T1 null muscle, we identified an increase in Akt activation in resting muscle as well as a significant increase in trkB.FL and Akt activation in response to contractile activity. On the basis of these findings, we conclude that the trkB signaling pathway might represent a novel target for intervention across diseases characterized by deficits in neuromuscular function.

Citing Articles

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Postnatal survival of phrenic motor neurons is promoted by BDNF/TrkB.FL signaling.

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References

McLachlan E, Martin A . Non-linear summation of end-plate potentials in the frog and mouse. J Physiol. 1981; 311:307-24. PMC: 1275411. DOI: 10.1113/jphysiol.1981.sp013586. View

Zhan W, Mantilla C, Sieck G . Regulation of neuromuscular transmission by neurotrophins. Sheng Li Xue Bao. 2003; 55(6):617-24. View

Troca-Marin J, Alves-Sampaio A, Montesinos M . An increase in basal BDNF provokes hyperactivation of the Akt-mammalian target of rapamycin pathway and deregulation of local dendritic translation in a mouse model of Down's syndrome. J Neurosci. 2011; 31(26):9445-55. PMC: 6623175. DOI: 10.1523/JNEUROSCI.0011-11.2011. View

Belluardo N, Westerblad H, Mudo G, Casabona A, Bruton J, Caniglia G . Neuromuscular junction disassembly and muscle fatigue in mice lacking neurotrophin-4. Mol Cell Neurosci. 2001; 18(1):56-67. DOI: 10.1006/mcne.2001.1001. View

Prakash Y, Iyanoye A, Ay B, Mantilla C, Pabelick C . Neurotrophin effects on intracellular Ca2+ and force in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2006; 291(3):L447-56. DOI: 10.1152/ajplung.00501.2005. View

Liu Y, Shen T, Randall W, Schneider M . Signaling pathways in activity-dependent fiber type plasticity in adult skeletal muscle. J Muscle Res Cell Motil. 2005; 26(1):13-21. DOI: 10.1007/s10974-005-9002-0. View

Li Z, Oh D, Nakamura K, Thiele C . Perifosine-induced inhibition of Akt attenuates brain-derived neurotrophic factor/TrkB-induced chemoresistance in neuroblastoma in vivo. Cancer. 2011; 117(23):5412-22. PMC: 3158972. DOI: 10.1002/cncr.26133. View

Del Castillo J, Katz B . Statistical factors involved in neuromuscular facilitation and depression. J Physiol. 1954; 124(3):574-85. PMC: 1366293. DOI: 10.1113/jphysiol.1954.sp005130. View

Mantilla C, Zhan W, Sieck G . Neurotrophins improve neuromuscular transmission in the adult rat diaphragm. Muscle Nerve. 2004; 29(3):381-6. DOI: 10.1002/mus.10558. View

10.

Lennon N, Kho A, Bacskai B, Perlmutter S, Hyman B, Brown Jr R . Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing. J Biol Chem. 2003; 278(50):50466-73. DOI: 10.1074/jbc.M307247200. View

11.

Kafitz K, Rose C, Thoenen H, Konnerth A . Neurotrophin-evoked rapid excitation through TrkB receptors. Nature. 1999; 401(6756):918-21. DOI: 10.1038/44847. View

12.

Cittadini A, Monti M, Iaccarino G, Di Rella F, Tsichlis P, Di Gianni A . Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling. Gene Ther. 2005; 13(1):8-19. PMC: 2999753. DOI: 10.1038/sj.gt.3302589. View

13.

Ogborn D, Gardiner P . Effects of exercise and muscle type on BDNF, NT-4/5, and TrKB expression in skeletal muscle. Muscle Nerve. 2009; 41(3):385-91. DOI: 10.1002/mus.21503. View

14.

Kato N, Tanaka T, Yamamoto K, Isomura Y . Enhancement of activity-dependent calcium increase by neurotrophin-4 in visual cortex pyramidal neurons. Brain Res. 1999; 832(1-2):179-83. DOI: 10.1016/s0006-8993(99)01474-2. View

15.

Kaplan D, Miller F . Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol. 2000; 10(3):381-91. DOI: 10.1016/s0959-4388(00)00092-1. View

16.

Barton E, Morris L, Musaro A, Rosenthal N, Sweeney H . Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice. J Cell Biol. 2002; 157(1):137-48. PMC: 2173262. DOI: 10.1083/jcb.200108071. View

17.

Dupont-Versteegden E, Houle J, Dennis R, Zhang J, Knox M, Wagoner G . Exercise-induced gene expression in soleus muscle is dependent on time after spinal cord injury in rats. Muscle Nerve. 2003; 29(1):73-81. DOI: 10.1002/mus.10511. View

18.

Blaauw B, Mammucari C, Toniolo L, Agatea L, Abraham R, Sandri M . Akt activation prevents the force drop induced by eccentric contractions in dystrophin-deficient skeletal muscle. Hum Mol Genet. 2008; 17(23):3686-96. DOI: 10.1093/hmg/ddn264. View

19.

Lieber R, Shah S, Friden J . Cytoskeletal disruption after eccentric contraction-induced muscle injury. Clin Orthop Relat Res. 2002; (403 Suppl):S90-9. DOI: 10.1097/00003086-200210001-00011. View

20.

Gonzalez M, Ruggiero F, Chang Q, Shi Y, Rich M, Kraner S . Disruption of Trkb-mediated signaling induces disassembly of postsynaptic receptor clusters at neuromuscular junctions. Neuron. 1999; 24(3):567-83. DOI: 10.1016/s0896-6273(00)81113-7. View