Premium
The role of denervation in cytokine‐mediated muscle dysfunction in muscles of old mice
Author(s) -
Staunton Caroline Amy,
Pollock Natalie,
Lightfoot Adam,
Vasilaki Aphrodite,
BarrettJolley Richard,
McArdle Anne,
Jackson Malcolm
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1009.4
Subject(s) - denervation , cxcl1 , in vivo , medicine , endocrinology , cytokine , neuromuscular junction , inflammation , chemistry , anatomy , biology , chemokine , neuroscience , microbiology and biotechnology
Age‐related loss of muscle mass and function occurs over a substantial portion of later life and greatly influences the quality of life of older people. The causes of this dysfunction are unknown, but substantial remodelling and loss of motor units and denervation are evident in muscles of old mice. Full denervation of muscle caused elevations in the rate of mitochondrial H 2 0 2 production. Data from our laboratory have demonstrated that H 2 0 2 was elevated in muscle at 3 days post‐denervation and remained significantly elevated for 10 days, compared with sham controls. Further work from our laboratory has shown that this increase in H 2 O 2 is also evident in the innervated portion of partially denervated muscle. The aim of this study was (1) to use intra‐vital imaging in Thy1‐CFP mice to determine the structure of peripheral axons and neuromuscular junctions in single muscle fibers in vivo and to simultaneously monitor H 2 0 2 in the muscle fibers using AAV6‐Hyper2‐Cyto mice; (2) to examine the downstream effects of increased H 2 O 2 , including NF‐kB activation and production of pro‐inflammatory cytokines in whole muscles and in individual fibers and (3) whether these processes contribute to age‐related muscle dysfunction. Data demonstrate that the increased H 2 O 2 in fully denervated muscle of adult mice was associated with activation of NF‐kB and increased production of pro‐inflammatory cytokines; IL‐6 (302% increase), MCP1 (324% increase) and CXCL1 (261% increase), all as early as 1 day post‐denervation (p<0.05, Students T‐Test), in a similar manner to quiescent muscles of old mice. These data suggest that denervation of individual muscle fibers in old mice results in significant elevations in H 2 O 2 production in both denervated and innervated fibers and that this may play a role in the increased activation of NF‐kB and local production of pro‐inflammatory cytokines seen in muscles of old mice. Additional studies will explore neuromuscular transmission using electrophysiology in single fibers to determine the effects of different degrees of loss of neuromuscular junction integrity on neuromuscular transmission and the relationship of this to H 2 0 2 production. Support or Funding Information Supported by the UK Medical Research Council.