181 - The Role of Denervation in Cytokine-Mediated Muscle Dysfunction in Old Mice

Abstract

Age-related loss of muscle mass and function greatly influences the quality of life of older people. Denervation and increases in pro-inflammatory cytokines are proposed to play a substantial role in this muscle dysfunction. Full denervation of muscle of adult mice causes an increase in the rate of mitochondrial peroxide production1 and data from our laboratory have further demonstrated that this peroxide generation by muscle remained significantly elevated for up to 10 days after denervation, compared with sham controls. Further data suggest that increased mitochondrial peroxide generation may mediate cytokine production by muscle cells2. We hypothesise that the denervation evident in some muscle fibres of old mice results in increased mitochondrial peroxide generation which in turn results in increased production of cytokines by muscle, further contributing to muscle dysfunction. The aim of this study was (1) to use intra-vital imaging in Thy1-CFP mice to examine the structure of peripheral axons and neuromuscular junctions in single muscle fibers in vivo and to monitor H2O2 generation by denervated muscle fibers using AAV6-Hyper2-Cyto injected mice and (2) to examine the effects of increased H2O2 on NF-κB activation and the production of pro-inflammatory cytokines in these fibers. Data demonstrated that the increased mitochondrial peroxide generation in fully denervated muscle of adult mice was associated with activation of NF-κB and increased production of pro-inflammatory cytokines including IL-6, MCP1 and CXCL1. These data suggest that denervation of individual muscle fibers in old mice may result in elevations in H2O2 production in both denervated and innervated fibers and that this may play a role in the increased activation of NF-κB and production of pro-inflammatory cytokines seen in muscles of old mice. Current work focuses on assessment of neuromuscular transmission using electrophysiology in single fibers to determine which age-related changes in neuromuscular junction structure are associated with a lack of neuromuscular activity and cytokine production. References Muller FL, et al 2007. Am J. Physiol. (Reg) 293:R1159-1168. Lightfoot AP, et al 2015. Redox biology. 6:253-259, 2015. Supported by the UK MRC and NIA (AG-20591).