VAPB/ALS8 MSP Ligands Regulate Striated Muscle Energy Metabolism Critical for Adult Survival in Caenorhabditis elegans

• Published in: PLoS genetics Vol. 9; no. 9; p. e1003738
• Main Authors: Han, Sung Min, El Oussini, Hajer, Scekic-Zahirovic, Jelena, Vibbert, Jack, Cottee, Pauline, Prasain, Jeevan K., Bellen, Hugo J., Dupuis, Luc, Miller, Michael A.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2013; Public Library of Science (PLoS)
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Bioenergetics; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans Proteins - metabolism; Disease; Drosophila; Drosophila - metabolism; Energy Metabolism; Feasibility studies; Forkhead Transcription Factors; Gene mutations; Genes; Genetic aspects; Genetic regulation; Humans; Insects; Ligands; Ligands (Biochemistry); Lipids; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolism; Mice; Mice, Knockout; Mitochondria; Mitochondria - pathology; Motor Neurons - metabolism; Muscle, Striated - metabolism; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - pathology; Neurons; Physiological aspects; Properties; Proteins; Proteomics; Rodents; Signal Transduction; Sperm; Striated muscle; Transcription Factors - metabolism; Vesicular Transport Proteins; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003738

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.