Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration.

Wenxuan Liu,Lan Wei-Lapierre,Mariela Cortés-Lopéz,Nicole D Paris,Robert T Dirksen,Alanna Klose,Morgan Flaherty,Pedro Miura,Aidi Tan,Sophie Forman,Joe V Chakkalakal

doi:10.7554/elife.26464

Abstract

Neuromuscular junction degeneration is a prominent aspect of sarcopenia, the age-associated loss of skeletal muscle integrity. Previously, we showed that muscle stem cells activate and contribute to mouse neuromuscular junction regeneration in response to denervation (Liu et al., 2015). Here, we examined gene expression profiles and neuromuscular junction integrity in aged mouse muscles, and unexpectedly found limited denervation despite a high level of degenerated neuromuscular junctions. Instead, degenerated neuromuscular junctions were associated with reduced contribution from muscle stem cells. Indeed, muscle stem cell depletion was sufficient to induce neuromuscular junction degeneration at a younger age. Conversely, prevention of muscle stem cell and derived myonuclei loss was associated with attenuation of age-related neuromuscular junction degeneration, muscle atrophy, and the promotion of aged muscle force generation. Our observations demonstrate that deficiencies in muscle stem cell fate and post-synaptic myogenesis provide a cellular basis for age-related neuromuscular junction degeneration and associated skeletal muscle decline.

Highlights

Age-related neuromuscular junction (NMJ, synapse between motor neuron and skeletal muscle cells) declines in rodents and humans manifest as altered pre-synaptic nerve terminal and abnormal postsynaptic morphology indicative of degeneration (Gonzalez-Freire et al, 2014; Oda, 1984; Wokke et al, 1990)
Complete denervation is not a prominent feature of aged skeletal muscles Aging is associated with an increased proportion of NMJs that display degenerated pre/post-synaptic morphologies in both tibialis anterior (TA) and diaphragm muscles (Figure 1A–E) (GonzalezFreire et al, 2014; Valdez et al, 2010, 2012)
Gene sets associated with acetylcholine receptor (AChR) activity and neurotransmission were highly enriched in 6M-Syn samples (Figure 1—figure supplement 1A and B) (Chakkalakal and Jasmin, 2003; Merlie and Sanes, 1985; Hippenmeyer et al, 2007; Kishi et al, 2005)

Summary

Introduction

Age-related neuromuscular junction (NMJ, synapse between motor neuron and skeletal muscle cells) declines in rodents and humans manifest as altered pre-synaptic nerve terminal and abnormal postsynaptic morphology indicative of degeneration (Gonzalez-Freire et al, 2014; Oda, 1984; Wokke et al, 1990). These disruptions are often associated with skeletal muscle dysfunction and disease, whether age-associated NMJ remodeling primarily reflects deterioration of target muscle cells or the peripheral nervous system is unknown (Kang and Lichtman, 2013; Banker et al, 1983; Li et al, 2011). Whether SCs contribute to the maintenance of aging NMJs, and if age-related SC loss primarily drives NMJ deterioration has not been tested

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