RRC ID 45983
Author Han SM, El Oussini H, Scekic-Zahirovic J, Vibbert J, Cottee P, Prasain JK, Bellen HJ, Dupuis L, Miller MA.
Title VAPB/ALS8 MSP ligands regulate striated muscle energy metabolism critical for adult survival in caenorhabditis elegans.
Journal PLoS Genet.
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.
Volume 9(9)
Pages e1003738
Published 2013
DOI 10.1371/journal.pgen.1003738
PII PGENETICS-D-13-00900
PMID 24039594
PMC PMC3764199
MeSH Amyotrophic Lateral Sclerosis / genetics Amyotrophic Lateral Sclerosis / metabolism* Amyotrophic Lateral Sclerosis / pathology Animals Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / metabolism Drosophila / metabolism Energy Metabolism* Forkhead Transcription Factors Humans Ligands Membrane Proteins / genetics* Membrane Proteins / metabolism Mice Mice, Knockout Mitochondria / pathology Motor Neurons / metabolism Motor Neurons / secretion Muscle, Striated / metabolism* Muscular Atrophy, Spinal / genetics Muscular Atrophy, Spinal / metabolism* Muscular Atrophy, Spinal / pathology Signal Transduction Transcription Factors / metabolism
IF 5.54
Times Cited 11
WOS Category GENETICS & HEREDITY
Resource
C.elegans tm1411