title: Bcl-2-associated autophagy regulator Naf-1 required for maintenance of skeletal muscle.
abstract: Nutrient-deprivation autophagy factor-1 (NAF-1) was identified as an endoplasmic reticulum (ER) BCL-2-interacting protein, which functions to mediate the ability of ER BCL-2 to antagonize Beclin 1-dependent autophagy and depress ER calcium stores. In humans, a point mutation in Naf-1 (synonyms: Cisd2, Eris, Miner1 and Noxp70) is responsible for the neurodegenerative disorder Wolfram Syndrome 2. Here, we describe the generation and characterization of the Naf-1 gene deletion in mice. Naf-1 null mice display discernable clinical signs of degeneration at 2-3 months of age, with early evidence of significant defects in the structure and performance of skeletal muscle. Skeletal muscles from Naf-1 knockout mice demonstrate a significant shift towards slow-twitch (type I) fibers and greater resistance to muscle fatigue. Force-generating capacity is dramatically reduced in Naf-1(-/-) muscle. Consistent with its role in ER BCL-2-mediated regulation of autophagy and calcium flux, these physiological deficiencies were accompanied by augmented autophagy and dysregulated calcium homeostasis. In contrast, this also included adaptive enlargement of mitochondria with extensive cristae structures. Thus, NAF-1, a BCL-2-associated autophagy regulator, is required for homeostatic maintenance of skeletal muscle. Our findings uncover a novel pathway that is required for normal muscle maintenance, which may ultimately provide a novel therapeutic target for treating certain muscle pathologies.
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada.
authors.forename: Natasha C
authors.initials: NC
authors.lastname: Chang
authors.forename: Mai
authors.initials: M
authors.lastname: Nguyen
authors.forename: Johanne
authors.initials: J
authors.lastname: Bourdon
authors.forename: Paul-André
authors.initials: PA
authors.lastname: Risse
authors.forename: James
authors.initials: J
authors.lastname: Martin
authors.forename: Gawiyou
authors.initials: G
authors.lastname: Danialou
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.forename: Basil J
authors.initials: BJ
authors.lastname: Petrof
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Shore
mesh_terms: D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D012261:Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C515811:Noxp70 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012261:Ribonucleoproteins; C052617:Bcl2 protein, mouse