Striking Denervation of Neuromuscular Junctions without Lumbar Motoneuron Loss in Geriatric Mouse Muscle

TLDR

Sarcopenia, the age‑related loss of skeletal muscle mass and function, is complex, poorly studied in mice, and involves myofibre denervation. This study compares the neuromuscular compartment of young (3 mo) and geriatric (29 mo) female C57Bl/6J mice to identify which components drive the marked NMJ and muscle changes that could be targeted to reduce sarcopenia. Geriatric mice show no loss of lumbar motoneuron cell bodies but exhibit a 2.5‑fold increase in fully denervated NMJs and Schwann cell deterioration in fast EDL, along with shifts toward faster TA and slower soleus fibre phenotypes, indicating complex NMJ and muscle alterations independent of motoneuron loss.

Abstract

Reasons for the progressive age-related loss of skeletal muscle mass and function, namely sarcopenia, are complex. Few studies describe sarcopenia in mice, although this species is the mammalian model of choice for genetic intervention and development of pharmaceutical interventions for muscle degeneration. One factor, important to sarcopenia-associated neuromuscular change, is myofibre denervation. Here we describe the morphology of the neuromuscular compartment in young (3 month) compared to geriatric (29 month) old female C57Bl/6J mice. There was no significant difference in the size or number of motoneuron cell bodies at the lumbar level (L1–L5) of the spinal cord at 3 and 29 months. However, in geriatric mice, there was a striking increase (by ∼2.5 fold) in the percentage of fully denervated neuromuscular junctions (NMJs) and associated deterioration of Schwann cells in fast extensor digitorum longus (EDL), but not in slow soleus muscles. There were also distinct changes in myofibre composition of lower limb muscles (tibialis anterior (TA) and soleus) with a shift at 29 months to a faster phenotype in fast TA muscle and to a slower phenotype in slow soleus muscle. Overall, we demonstrate complex changes at the NMJ and muscle levels in geriatric mice that occur despite the maintenance of motoneuron cell bodies in the spinal cord. The challenge is to identify which components of the neuromuscular system are primarily responsible for the marked changes within the NMJ and muscle, in order to selectively target future interventions to reduce sarcopenia.