title: VAPB/ALS8 MSP ligands regulate striated muscle energy metabolism critical for adult survival in caenorhabditis elegans.
abstract: Mutations in VAPB/ALS8 are associated with amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), two motor neuron diseases that often include alterations in energy metabolism. We have shown that C. elegans and Drosophila neurons secrete a cleavage product of VAPB, the N-terminal major sperm protein domain (vMSP). Secreted vMSPs signal through Roundabout and Lar-like receptors expressed on striated muscle. The muscle signaling pathway localizes mitochondria to myofilaments, alters their fission/fusion balance, and promotes energy production. Here, we show that neuronal loss of the C. elegans VAPB homolog triggers metabolic alterations that appear to compensate for muscle mitochondrial dysfunction. When vMSP levels drop, cytoskeletal or mitochondrial abnormalities in muscle induce elevated DAF-16, the Forkhead Box O (FoxO) homolog, transcription factor activity. DAF-16 promotes muscle triacylglycerol accumulation, increases ATP levels in adults, and extends lifespan, despite reduced muscle mitochondria electron transport chain activity. Finally, Vapb knock-out mice exhibit abnormal muscular triacylglycerol levels and FoxO target gene transcriptional responses to fasting and refeeding. Our data indicate that impaired vMSP signaling to striated muscle alters FoxO activity, which affects energy metabolism. Abnormalities in energy metabolism of ALS patients may thus constitute a compensatory mechanism counterbalancing skeletal muscle mitochondrial dysfunction.
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama School of Medicine, Birmingham, Alabama, United States of America.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Han
authors.forename: Hajer
authors.initials: H
authors.lastname: El Oussini
authors.forename: Jelena
authors.initials: J
authors.lastname: Scekic-Zahirovic
authors.forename: Jack
authors.initials: J
authors.lastname: Vibbert
authors.forename: Pauline
authors.initials: P
authors.lastname: Cottee
authors.forename: Jeevan K
authors.initials: JK
authors.lastname: Prasain
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
authors.forename: Luc
authors.initials: L
authors.lastname: Dupuis
authors.forename: Michael A
authors.initials: MA
authors.lastname: Miller
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D004330:Drosophila / Q000378:metabolism; D004734:Energy Metabolism; D051858:Forkhead Transcription Factors; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism; D054792:Muscle, Striated / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D033921:Vesicular Transport Proteins
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D008024:Ligands; D008565:Membrane Proteins; D014157:Transcription Factors; C529892:VAPB protein, mouse; D033921:Vesicular Transport Proteins; C108831:daf-16 protein, C elegans
references.citation: Aging Cell. 2011 Aug;10(4):699-710
references.pmid: 21501374
references.citation: Neurology. 2008 Mar 25;70(13):1004-9
references.pmid: 18199832
references.citation: Aging (Albany NY). 2010 Oct;2(10):742-7
references.pmid: 20975207
references.citation: Science. 2002 Dec 20;298(5602):2398-401
references.pmid: 12471266
references.citation: Muscle Nerve. 2006 Dec;34(6):731-9
references.pmid: 16967488
references.citation: Cell. 2011 Feb 4;144(3):389-401
references.pmid: 21295699
references.citation: Arch Neurol. 2010 Jul;67(7):849-54
references.pmid: 20625092
references.citation: Genes Dev. 2003 Jan 15;17(2):187-200
references.pmid: 12533508
references.citation: Traffic. 2011 Feb;12(2):218-31
references.pmid: 21062391
references.citation: Nature. 2003 Jul 17;424(6946):277-83
references.pmid: 12845331
references.citation: Endocrinology. 2008 May;149(5):2293-305
references.pmid: 18202130
references.citation: J Gerontol A Biol Sci Med Sci. 2006 May;61(5):444-60
references.pmid: 16720740
references.citation: Neurology. 2013 Feb 26;80(9):829-38
references.pmid: 23390184
references.citation: Genetics. 2008 Feb;178(2):903-18
references.pmid: 18245330
references.citation: J Biol Chem. 2002 Aug 16;277(33):29908-18
references.pmid: 12023275
references.citation: Nat Genet. 2006 Feb;38(2):251-7
references.pmid: 16380712
references.citation: Exp Gerontol. 2006 Oct;41(10):910-21
references.pmid: 16934425
references.citation: FASEB J. 2006 Mar;20(3):583-5
references.pmid: 16507768
references.citation: J Biol Chem. 2010 Jan 1;285(1):705-12
references.pmid: 19889637
references.citation: Can J Biochem Physiol. 1959 Aug;37(8):911-7
references.pmid: 13671378
references.citation: Trends Cell Biol. 2008 Jun;18(6):282-90
references.pmid: 18468439
references.citation: Hum Mol Genet. 2013 Jun 15;22(12):2350-60
references.pmid: 23446633
references.citation: Cytometry. 1999 Aug 1;36(4):355-8
references.pmid: 10404152
references.citation: Am J Hum Genet. 2004 Nov;75(5):822-31
references.pmid: 15372378
references.citation: Methods. 2003 Aug;30(4):313-21
references.pmid: 12828945
references.citation: Hum Mol Genet. 2013 Jul 1;22(13):2689-704
references.pmid: 23492670
references.citation: PLoS One. 2011;6(10):e26066
references.pmid: 21998752
references.citation: Neurobiol Aging. 2010 Jun;31(6):969-85
references.pmid: 18701194
references.citation: Cell. 2008 Jun 13;133(6):963-77
references.pmid: 18555774
references.citation: PLoS One. 2013;8(2):e57739
references.pmid: 23469062
references.citation: Hum Mol Genet. 2012 Mar 15;21(6):1299-311
references.pmid: 22131369
references.citation: Antioxid Redox Signal. 2011 Feb 15;14(4):649-61
references.pmid: 20615072
references.citation: Dev Dyn. 2010 May;239(5):1405-12
references.pmid: 20140911
references.citation: Mol Biol Cell. 2008 Sep;19(9):3871-84
references.pmid: 18614794
references.citation: Nat Genet. 2003 Jan;33(1):40-8
references.pmid: 12447374
references.citation: J Biol Chem. 2004 Sep 24;279(39):41114-23
references.pmid: 15272020
references.citation: FASEB J. 1999 Aug;13(11):1385-93
references.pmid: 10428762
references.citation: Genome Res. 2005 May;15(5):603-15
references.pmid: 15837805
references.citation: Neurobiol Aging. 2005 May;26(5):689-96
references.pmid: 15708444
references.citation: Development. 2003 Oct;130(20):4761-8
references.pmid: 12952898
references.citation: J Biol Chem. 2005 Apr 8;280(14):14097-104
references.pmid: 15668246
references.citation: Nat Genet. 2001 Jun;28(2):139-45
references.pmid: 11381260
references.citation: Genetics. 1974 May;77(1):71-94
references.pmid: 4366476
references.citation: J Neurosci. 2007 Sep 5;27(36):9801-15
references.pmid: 17804640
references.citation: J Biol Chem. 2005 Feb 18;280(7):5934-44
references.pmid: 15545272
references.citation: Mech Ageing Dev. 2002 Jan;123(2-3):105-19
references.pmid: 11718805
references.citation: Hum Mol Genet. 2008 Jun 1;17(11):1517-26
references.pmid: 18263603
references.citation: Hum Mol Genet. 2011 Sep 15;20(18):3642-52
references.pmid: 21685205
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12378-83
references.pmid: 14530391
references.citation: Biochem Res Int. 2012;2012:841362
references.pmid: 22195283
references.citation: Cell. 1998 Mar 6;92(5):633-43
references.pmid: 9506518
references.citation: Development. 2005 Aug;132(15):3357-69
references.pmid: 15975936
references.citation: Aging Cell. 2003 Apr;2(2):111-21
references.pmid: 12882324
references.citation: J Lipid Res. 2011 Jun;52(6):1281-1293
references.pmid: 21421847
references.citation: PLoS Biol. 2007 Oct 2;5(10):e259
references.pmid: 17914900
references.citation: Ann N Y Acad Sci. 2009 Jul;1170:688-92
references.pmid: 19686213
references.citation: Lancet. 2011 Mar 12;377(9769):942-55
references.pmid: 21296405
references.citation: Lancet Neurol. 2011 Jan;10(1):75-82
references.pmid: 21035400
references.citation: Nat Cell Biol. 2006 Oct;8(10):1143-8
references.pmid: 16998478
references.citation: Dev Cell. 2009 Oct;17(4):459-69
references.pmid: 19853560
references.citation: PLoS One. 2011 Jan 17;6(1):e14507
references.pmid: 21264209
references.citation: Nature. 2002 Oct 24;419(6909):808-14
references.pmid: 12397350
references.citation: J Neurol. 2011 Apr;258(4):613-7
references.pmid: 21128082
references.citation: Dev Cell. 2012 Feb 14;22(2):348-62
references.pmid: 22264801
references.citation: J Cell Biol. 2002 Aug 19;158(4):639-46
references.pmid: 12186849
references.citation: J Biol Chem. 2010 Dec 17;285(51):40266-81
references.pmid: 20940299
references.citation: Mol Biol Cell. 1999 Dec;10(12):4311-26
references.pmid: 10588660
references.citation: Dev Biol. 2010 Jun 1;342(1):96-107
references.pmid: 20380830
references.citation: Dev Dyn. 2010 May;239(5):1265-81
references.pmid: 20034089