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Exosomal Signaling by Skeletal Muscle: Role in Neuromuscular Ageing
Author(s) -
Hemmings Kay,
Pollock Natalie,
Owen Euan,
Mora Silvia,
Brooks Susan,
McArdle Anne
Publication year - 2020
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.2020.34.s1.05506
Subject(s) - proteostasis , exosome , microbiology and biotechnology , heat shock protein , skeletal muscle , biology , microvesicles , hsp70 , extracellular , myocyte , neuromuscular junction , contraction (grammar) , chemistry , endocrinology , biochemistry , neuroscience , microrna , gene
Muscle mass and function are reduced with age in mammals and this is associated with disrupted neuromuscular interactions. Skeletal muscle mounts a robust stress response to contractions by an increased expression of Heat Shock Proteins (HSPs) that facilitate muscle remodeling, promote protein folding and clearance of damaged proteins. In contrast, other cell types including neuronal cells, are unable to mount a stress response. It has been proposed that HSPs may be transferred from one cell type to another in exosomes to maintain proteostasis in the recipient cells. Thus, speculation that the robust HSP response by muscle provides support to peripheral neuronal cells via exosomal transfer of HSPs is tempting. However, HSP generation by muscle following contractions is attenuated in old mice and humans. We hypothesise that inability of muscles of old mice to produce HSPs in response to contraction results in altered exosomal HSP transfer, and therefore a failure to maintain proteostasis in motor neurons, resulting in neuronal and muscle degeneration (1). Muscle fibres were isolated from flexor digitorum bravis (FDB) muscles of adult (6–8 month) and old (24–26 month) mice, and initiated to contract using a non‐damaging electrical stimulation protocol (2). Media was collected from quiescent fibres, and fibres immediately following contraction, and Extracellular Vesicles (EVs) purified using a Total Exosome Isolation kit (Thermo). NanoSight analysis was used to characterise the size and number of the EVs. Total protein content was determined and HSP levels were analysed by western blotting. Data demonstrated no significant difference in the total number of EVs released from quiescent fibres from adult and old mice, along with a similar increase in EVs released by muscle fibres of adult (2.7 fold) and old mice (3.1 fold) immediately following contraction compared with quiescent fibres. In contrast, the size distribution of the EVs from fibres of old mice was altered compared with EVs from adult fibres, and the total protein content of EVs was significantly less (40% decrease) in those released by quiescent old fibres compared with EVs of quiescent adult fibres. The lower protein content for EVs from old compared with adult fibres was maintained following stimulation. A 2.5 fold increase in HSP25 and a substantial increase in HSP60 content (from undetectable levels) was seen in EVs from fibres of adult mice immediately following contraction. In contrast, preliminary data suggested that the HSP60 content of EVs produced by quiescent muscle fibres from old mice is already elevated, with little further increase following contraction in a similar manner to muscles in vivo (3). Additional data will examine the uptake of EVs by neuronal cells and the effect of age of donor on their uptake ability. Support or Funding Information With thanks to National Institute of Ageing (AG051442) and the University of Liverpool for their generous support.1 McArdle , A. and Jackson , MJ. ( 2017 ). Essays Biochem 61 , 339 – 348 . 2 Palomero , J. et al ( 2008 ), Antioxid Redox Signal. 10 : 1463 – 743 Vasilaki , A. et al ( 2006 ). Mech Ageing Dev. 127 ( 11 ): 830 – 9