Ageing and neurotrophic signalling effects on diaphragm neuromuscular function

Abstract

Key points: Sarcopenia of the diaphragm muscle, i.e. loss of muscle force and size with increasing age, may contribute to respiratory impairment in old age but the exact mechanisms underlying this are currently unknown. Across the lifespan in mice there is worsening neuromuscular function of the diaphragm muscle, specifically reduced force and impaired neuromuscular transmission. We tested the hypothesis that age-related changes to the diaphragm muscle depend on brain-derived neurotrophic factor (BDNF), acting through its high affinity receptor. BDNF improves neuromuscular transmission in the diaphragm muscle into early old age, but not older ages. Inhibition of BDNF signalling impairs neuromuscular transmission only in young adult mice. Our results suggest that the loss of endogenous BDNF precedes reduced activity of the high affinity receptor tropomyosin-related kinase receptor B in the ageing mouse diaphragm muscle. The age-related mechanisms underlying sarcopenia are largely unknown. We hypothesize that age-related neuromuscular changes depend on brain-derived neurotrophic factor (BDNF) acting through the tropomyosin-related kinase receptor B (TrkB). Maximal specific force and neuromuscular transmission failure were assessed at 6, 18 and 24 months following control, BDNF or phosphoprotein phosphatase 1 derivative (1NMPP1) treatment in male TrkBF616A mice. Phosphoprotein phosphatase-1 derivatives such as 1NMPP1 inhibit TrkB kinase activity as a result of this single amino acid mutation in the ATP binding domain. Maximal twitch and isometric tetanic force were reduced at 24 months compared to 6 and 18 months (P < 0.001). Neuromuscular transmission failure significantly increased at 18 and 24 months compared to 6 months (age × treatment interaction: P < 0.001). Neuromuscular transmission was improved following BDNF at 6 and 18 months and was impaired only at 6 months following 1NMPP1 treatment. Age and inhibition of TrkB kinase activity had similar effects on neuromuscular transmission failure, supporting a critical role for BDNF/TrkB signalling on neuromuscular changes in ageing. These results suggest that an age-related loss of endogenous BDNF precedes reductions in TrkB kinase activity in the diaphragm muscle. The Journal of Physiology