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.

Hypothalamic Sirt1 protects terminal Schwann cells and neuromuscular junctions from age‐related morphological changes

“…These findings suggest minimal motor nerve sprouting associated with remodeling, possibly resulting in permanent denervation for some muscle fibers. High numbers of denervated or partially innervated synapses with extremes of age have been previously described by others (Banker, Kelly & Robbins, 1983; Chai et al., 2011; Valdez, Tapia, Lichtman, Fox & Sanes, 2012). …”

“…Fragmentation of AChRs was noted in our study, and irregular and granular endplate fragmentation has been previously noted in aged mice (Balice‐Gordon, 1997; Chai et al., 2011; Pannerec et al., 2016; Valdez et al., 2012; Willadt, Nash & Slater, 2016). Pannerec et al.…”

“…NMJ innervation (mostly or completely apposed endplates, stained with NF200/SV2 Abs, α‐BTX, and DAPI) was determined by classifying each NMJ in a given field of view as fully innervated (nerve terminal completely overlies α‐BTX), partially innervated (nerve terminal only partially covers α‐BTX), or vacant (no nerve terminal overlying the endplate) (Valdez et al., 2012). To ensure that lack of nerve terminal staining is not simply due to poor antibody penetration, surrounding NMJs and endplates were carefully observed.…”

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

“…NMJ analysis was performed by imaging over 100 NMJs per mouse in 10–12 different regions of the EDL muscles. Unpaired t tests were used to compare NMJs of wild‐type mice with animals having altered levels of SIRT1 from the same experimental cohort with litter‐ and gender‐matched sib pairs as described in prior studies (Valdez et al, 2010, 2012 ). Survival curve analysis was performed using log‐rank (Mantel–Cox) testing and Kaplan–Meier curves.…”

“…A shared feature of normal aging and ALS is the progressive degeneration of the neuromuscular junction (NMJ), a synapse that is essential for the function of alpha‐motor neurons and skeletal muscles (Valdez, Tapia, Lichtman, Fox, & Sanes, 2012). With advancing age or ALS, the NMJ acquires deleterious structural and functional features that include the loss of synaptic vesicles and dysregulated neurotransmitter release that lead to the degeneration of motor axon nerve endings (Jang & Van Remmen, 2011; Valdez et al, 2010; Arbour, 2015).…”