The importance of proper neuromuscular innervation in muscle maintenance, ageing and disease

Innervation of neuromuscular junctions (NMJs) is of central importance for skeletal muscle function, maturation and maintenance of muscle mass. Two main situations of muscle disorders are examined in mice, with a focus on NMJs: i) sarcopenia – the agerelated loss of skeletal muscle mass and function; ii) muscular dystrophies ‐ using the lamin A/C (Lmna) null and mdx mice, combined with mice lacking the nuclear protein SUN1. One study (paper published) shows marked denervation of NMJs in geriatric normal mice, with a strong association with sarcopenia. The next study (paper prepared for submission) investigated 2 interventions to prevent sarcopenia; voluntary lifetime exercise training +/‐ transgenic overexpression of IGF‐1 in skeletal muscles. Results showed that exercise, but not increased IGF‐1 prevented sarcopenia (loss of muscle mass) in geriatric mice. The impact of innervation was also investigated in muscles of the Lmna‐/‐ mouse, and results showed defective NMJ formation may be responsible for the immaturity of Lmna‐/‐ myofibres since the Lmna‐/‐Sun1‐/‐ mouse which had significantly improved NMJs morphology also had improved muscle mass and maturity; implicating lamin A and SUN1 in the establishment of NMJs and development of skeletal muscle. Preliminary experiments suggested that SUN1 may play a role in myogenesis as muscle autografts in Sun1‐/‐ mice had delayed regeneration. The absence of SUN1 in novel mdx‐Sun1‐/‐ mice suggested potential benefits on dystropathology although further studies are required. The future challenge is to further investigate interventions for sarcopenia and to define the roles that nuclear membrane proteins play in innervation and muscle function.