title: Shared resistance to aging and ALS in neuromuscular junctions of specific muscles.
abstract: Normal aging and neurodegenerative diseases both lead to structural and functional alterations in synapses. Comparison of synapses that are generally similar but respond differently to insults could provide the basis for discovering mechanisms that underlie susceptibility or resistance to damage. Here, we analyzed skeletal neuromuscular junctions (NMJs) in 16 mouse muscles to seek such differences. We find that muscles respond in one of three ways to aging. In some, including most limb and trunk muscles, age-related alterations to NMJs are progressive and extensive during the second postnatal year. NMJs in other muscles, such as extraocular muscles, are strikingly resistant to change. A third set of muscles, including several muscles of facial expression and the external anal sphinter, succumb to aging but not until the third postnatal year. We asked whether susceptible and resistant muscles differed in rostrocaudal or proximodistal position, source of innervation, motor unit size, or fiber type composition. Of these factors, muscle innervation by brainstem motor neurons correlated best with resistance to age-related decline. Finally, we compared synaptic alterations in normally aging muscles to those in a mouse model of amyotrophic lateral sclerosis (ALS). Patterns of resistance and susceptibility were strikingly correlated in the two conditions. Moreover, damage to NMJs in aged muscles correlated with altered expression and distribution of CRMP4a and TDP-43, which are both altered in motor neurons affected by ALS. Together, these results reveal novel structural, regional and molecular parallels between aging and ALS.
authors.affiliation: Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Gregorio
authors.initials: G
authors.lastname: Valdez
authors.forename: Juan C
authors.initials: JC
authors.lastname: Tapia
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Lichtman
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fox
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sanes
mesh_terms: D000375:Aging; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000294:innervation* / Q000473:pathology; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism* / Q000473:pathology; D011950:Receptors, Cholinergic / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: C526904:Dpysl3 protein, mouse; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D011950:Receptors, Cholinergic; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1