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Apocynin prevents cigarette smoking-induced loss of skeletal muscle mass and function by preserving proteostatic signalling
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  • Stanley Chan,
  • Ivan Bernardo,
  • Chanelle Mastronardo,
  • Huei Seow,
  • Kevin Mou,
  • Aleksandar Dobric,
  • Kurt Brassington,
  • Simone De Luca,
  • Stavros Selemidis,
  • Steven Bozinovski,
  • Ross Vlahos
Stanley Chan
RMIT University
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Ivan Bernardo
RMIT University
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Chanelle Mastronardo
RMIT University
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Huei Seow
RMIT University
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Kevin Mou
RMIT University
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Aleksandar Dobric
RMIT University
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Kurt Brassington
RMIT University
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Simone De Luca
RMIT University
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Stavros Selemidis
RMIT University
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Steven Bozinovski
RMIT University
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Ross Vlahos
RMIT University
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Abstract

Background and Purpose: Cigarette smoking (CS) is the major risk factor for developing COPD and related skeletal muscle dysfunction. It has been postulated that CS exposure may directly causes muscle dysfunction via the induction of oxidative stress. The present study examined the effect of a potent Nox inhibitor and ROS scavenger, apocynin on CS-induced muscle dysfunction. Experimental Approach: Male BALB/c mice were exposed to either room air (sham) or CS generated from 9 cigarettes per day, 5 days a week for 8 weeks with or without apocynin treatment (5 mg·kg-1 w/v, intraperitoneal injection). C2C12 myotubes exposed to either hydrogen peroxide (H2O2) or water-soluble cigarette smoke extract (CSE) with or without apocynin (500 nM), was set up as an experimental model in vitro. Key Results: Eight weeks of CS exposure caused significant lung inflammation and muscle dysfunction in mice; evidenced by a 10% loss in muscle mass and 54% loss in contractile function of tibialis anterior, attributable to altered myogenic homeostasis and protein oxidation. These effects were prevented by apocynin administration. In C2C12 myotubes, direct exposure to H2O2 or CSE caused myofiber wasting, which was associated with altered myogenic homeostasis marked by ~50% loss in muscle-derived insulin-like growth factor (IGF)-1 and 1.5-fold increase in myostatin expression. Apocynin treatment completely attenuated CSE-induced Nox2 expression, preserving muscle-derived IGF-1 expression and downstream mammalian target of rapamycin (mTOR) signaling pathway, thereby preventing myofiber wasting. Conclusion and Implications: Targeted pharmacological inhibition of Nox-derived ROS may alleviate the lung and systemic manifestations in smokers with COPD.

Peer review status:Published

07 Oct 2020Submitted to British Journal of Pharmacology
18 Oct 2020Submission Checks Completed
18 Oct 2020Assigned to Editor
21 Oct 2020Reviewer(s) Assigned
11 Nov 2020Review(s) Completed, Editorial Evaluation Pending
17 Nov 2020Editorial Decision: Revise Minor
20 Dec 20201st Revision Received
21 Dec 2020Assigned to Editor
21 Dec 2020Submission Checks Completed
27 Dec 2020Reviewer(s) Assigned
28 Jan 2021Review(s) Completed, Editorial Evaluation Pending
28 Jan 2021Editorial Decision: Revise Minor
07 Mar 20212nd Revision Received
08 Mar 2021Submission Checks Completed
08 Mar 2021Assigned to Editor
10 Mar 2021Reviewer(s) Assigned
23 Mar 2021Review(s) Completed, Editorial Evaluation Pending
24 Mar 2021Editorial Decision: Accept
04 Apr 2021Published in British Journal of Pharmacology. 10.1111/bph.15482