The effect of lengthening contractions on neuromuscular junction structure in adult and old mice.

Aphrodite Vasilaki,Anne Mcardle,Anna Kayani,Natalie Pollock,Giorgos K Sakellariou,Ifigeneia Giakoumaki,Malcolm J Jackson,Timothy Pearson,Katarzyna Goljanek-Whysall

doi:10.1007/s11357-016-9937-7

Aphrodite Vasilaki, Anne Mcardle + Show 7 more

Open Access

https://doi.org/10.1007/s11357-016-9937-7

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Journal: GeroScience	Publication Date: Jul 29, 2016
Citations: 21	License type: CC BY 4.0

Affiliation: University of Liverpool

Abstract

Skeletal muscles of old mice demonstrate a profound inability to regenerate fully following damage. Such a failure could be catastrophic to older individuals where muscle loss is already evident. Degeneration and regeneration of muscle fibres following contraction-induced injury in adult and old mice are well characterised, but little is known about the accompanying changes in motor neurons and neuromuscular junctions (NMJs) following this form of injury although defective re-innervation of muscle following contraction-induced damage has been proposed to play a role in sarcopenia. This study visualised and quantified structural changes to motor neurons and NMJs in Extensor digitorum longus (EDL) muscles of adult and old Thy1-YFP transgenic mice during regeneration following contraction-induced muscle damage. Data demonstrated that the damaging contraction protocol resulted in substantial initial disruption to NMJs in muscles of adult mice, which was reversed entirely within 28 days following damage. In contrast, in quiescent muscles of old mice, ∼15 % of muscle fibres were denervated and ∼80 % of NMJs showed disruption. This proportion of denervated and partially denervated fibres remained unchanged following recovery from contraction-induced damage in muscles of old mice although ∼25 % of muscle fibres were completely lost by 28 days post-contractions. Thus, in old mice, the failure to restore full muscle force generation that occurs following damage does not appear to be due to any further deficit in the percentage of disrupted NMJs, but appears to be due, at least in part, to the complete loss of muscle fibres following damage.

Highlights

During ageing, skeletal muscles become smaller and weaker such that, in humans, by age 70, the crosssectional area of skeletal muscle is reduced by 25– 30 % and muscle strength is reduced by 30–40 % (Porter et al 1995)
It has been proposed that multiple damaging insults may be a key mechanism leading to loss of muscle fibres during ageing (Ehrhardt and Morgan 2005; Shi and Garry 2006), a process which contributes substantially to sarcopenia, the role of failed regeneration in this process is controversial since Fry et al have shown that depleting muscle satellite cells has a severe effect on regenerative capacity of muscle, this has little effect on sarcopenia (Fry et al 2015)
This study has used a well-established rodent model of muscle damage to test the hypotheses that (i) lengthening contraction-induced damage to muscles is associated with disruption of the innervation of muscle fibres that would be fully reversed during regeneration in adult mice, but that (ii) the late stage failure in ability of muscles from old mice to recover their ability to generate force following lengthening contractions is associated with a failure to appropriately re-innervate regenerated muscle fibres

Summary

Introduction

Skeletal muscles become smaller and weaker such that, in humans, by age 70, the crosssectional area of skeletal muscle is reduced by 25– 30 % and muscle strength is reduced by 30–40 % (Porter et al 1995). The muscle fibres that remain show an increased susceptibility to damage and a substantially reduced ability to fully regenerate following damage (Brooks and Faulkner 1990; Kayani et al 2008; McArdle et al 2004), potentially resulting in a permanent functional deficit when damage occurs. This failure of muscle from older individuals to regenerate fully following damage could be catastrophic to older individuals. It has been proposed that multiple damaging insults may be a key mechanism leading to loss of muscle fibres during ageing (Ehrhardt and Morgan 2005; Shi and Garry 2006), a process which contributes substantially to sarcopenia, the role of failed regeneration in this process is controversial since Fry et al have shown that depleting muscle satellite cells has a severe effect on regenerative capacity of muscle, this has little effect on sarcopenia (Fry et al 2015)

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