Age-related fragmentation of the motor endplate is not associated with impaired neuromuscular transmission in the mouse diaphragm

Abstract

As mammals age, their neuromuscular junctions (NMJs) gradually change their form, acquiring an increasingly fragmented appearance consisting of numerous isolated regions of synaptic differentiation. It has been suggested that this remodelling is associated with impairment of neuromuscular transmission, and that this contributes to age-related muscle weakness in mammals, including humans. The underlying hypothesis, that increasing NMJ fragmentation is associated with impaired transmission, has never been directly tested. Here, by comparing the structure and function of individual NMJs, we show that neuromuscular transmission at the most highly fragmented NMJs in the diaphragms of old (26–28 months) mice is, if anything, stronger than in middle-aged (12–14 months) mice. We suggest that NMJ fragmentation per se is not a reliable indicator of impaired neuromuscular transmission.

Morphological Regeneration and Functional Recovery of Neuromuscular Junctions after Tourniquet-Induced Injuries in Mouse Hindlimb

“…In the present study, although morphological changes of nAChR clusters were not as rapid as motor nerve degeneration, the removal of nAChRs from the skeletal muscle membrane gradually increased the number of fragments per nAChR cluster and decreased the area per fragment in the nAChR cluster with longer TR time (Figure 3). While criteria such as “5 or more” fragments have been used to classify the nAChR cluster as either “fragmented” or “non-fragmented” nAChR clusters (Valdez et al, 2010; Falk et al, 2015; Willadt et al, 2016), our findings demonstrate that over half of nAChR clusters were still fragmented in 6-wk TR, although motor nerve innervation to nAChR clusters and motor nerve terminal occupancy in NMJs were recovered to normal levels.…”

“…Both morphological alterations of NMJs (motor nerve terminals and nAChR clusters) and resulting of sciatic nerve stimulated-EPPs during the TR suggest that motor nerve denervation could be mainly involved in disability of NMJ transmission during early stage of TR, while fragmentation of nAChR clusters possibly is the key factor that causes inefficiency of NMJ transmission during late-stage of TR. Some previous studies have shown that fragmentation of an individual nAChR cluster might correlate with a decline in efficacy of the neuromuscular transmission in pathophysiological states (Maselli et al, 1995; Gonzalez-Freire et al, 2014; Steinbeck et al, 2015; Vescovo, 2015; Willadt et al, 2016). Our current study further demonstrates that dysfunction of NMJ transmission is mediated by both motor nerve denervation and the fragmentation of nAChR clusters during TR.…”

What is Normal? Neuromuscular junction reinnervation after nerve injury

“…The reason for persistence of this morphological difference as well as the functional implications, however, are unknown. Importantly, fragmented endplates have been shown to have no decline in synaptic transmission in aged mice . Any of these morphological changes could easily be interpreted as abnormal in different experimental conditions or as a result of treatment effects.…”

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

“…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.…”

“…The increased endplate fragmentation noted by Willadt et al. (2016) did not correlate with function; compound muscle action potential (CMAP) amplitude was stable with age (Willadt et al., 2016). Similarly, the absence of nerve terminals in 40% of NMJs in 34‐month‐old mice did not result in major physiological changes compared to young (8‐ to 12‐month‐old) mice (Banker et al., 1983).…”