title: Klotho and smoking--An interplay influencing the skeletal muscle function deficits that occur in COPD.
abstract: BACKGROUND
  Klotho is an 'anti-ageing' hormone and transmembrane protein; Klotho deficient mice develop a similar ageing phenotype to smokers including emphysema and muscle wasting. The objective of this study was to evaluate skeletal muscle and circulating Klotho protein in smokers and COPD patients and to relate Klotho levels to relevant skeletal muscle parameters. We sought to validate our findings by undertaking complimentary murine studies.
  
  
  METHODS
  Fat free mass, quadriceps strength and spirometry were measured in 87 participants (61 COPD, 13 'healthy smokers' and 13 never smoking controls) in whom serum and quadriceps Klotho protein levels were also measured. Immunohistochemistry was performed to demonstrate the location of Klotho protein in human skeletal muscle and in mouse skeletal muscle in which regeneration was occurring following injury induced by electroporation. In a separate study, gastrocnemius Klotho protein was measured in mice exposed to 77 weeks of smoke or sham air.
  
  
  RESULTS
  Quadriceps Klotho levels were lower in those currently smoking (p = 0.01), irrespective of spirometry, but were not lower in patients with COPD. A regression analysis identified current smoking status as the only independent variable associated with human quadriceps Klotho levels, an observation supported by the finding that smoke exposed mice had lower gastrocnemius Klotho levels than sham exposed mice (p = 0.005). Quadriceps Klotho levels related to local oxidative stress but were paradoxically higher in patients with established muscle wasting or weakness; the unexpected relationship with low fat free mass was the only independent association. Within locomotor muscle, Klotho localized to the plasma membrane and to centralized nuclei in humans and in mice with induced muscle damage. Serum Klotho had an independent association with quadriceps strength but did not relate to quadriceps Klotho levels or to spirometric parameters.
  
  
  CONCLUSIONS
  Klotho is expressed in skeletal muscle and levels are reduced by smoking. Despite this, quadriceps Klotho protein expression in those with established disease appears complex as levels were paradoxically elevated in COPD patients with established muscle wasting. Whilst serum Klotho levels were not reduced in smokers or COPD patients and were not associated with quadriceps Klotho protein, they did relate to quadriceps strength.
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust and Imperial College, UK; Imperial College London, UK.
authors.forename: M S
authors.initials: MS
authors.lastname: Patel
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust and Imperial College, UK; Imperial College London, UK.
authors.forename: A V
authors.initials: AV
authors.lastname: Donaldson
authors.affiliation: Imperial College London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Lewis
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust and Imperial College, UK; Imperial College London, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Natanek
authors.affiliation: Imperial College London, UK.
authors.forename: J Y
authors.initials: JY
authors.lastname: Lee
authors.affiliation: INR, AstraZeneca, Mölndal, Sweden.
authors.forename: Y M
authors.initials: YM
authors.lastname: Andersson
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust and Imperial College, UK; Imperial College London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Haji
authors.affiliation: INR, AstraZeneca, Mölndal, Sweden.
authors.forename: S G
authors.initials: SG
authors.lastname: Jackson
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Bolognese
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Foley
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Podolin
authors.affiliation: INR, AstraZeneca, Mölndal, Sweden.
authors.forename: P L B
authors.initials: PL
authors.lastname: Bruijnzeel
authors.affiliation: NIHR Comprehensive Biomedical Research Centre, Guy's & St Thomas' NHS Foundation Trust and King's College London, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Hart
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust and Imperial College, UK; Imperial College London, UK.
authors.forename: N S
authors.initials: NS
authors.lastname: Hopkinson
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust and Imperial College, UK; Imperial College London, UK.
authors.forename: W D-C
authors.initials: WD
authors.lastname: Man
authors.affiliation: Imperial College London, UK.
authors.forename: P R
authors.initials: PR
authors.lastname: Kemp
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust and Imperial College, UK; Imperial College London, UK. Electronic address: m.polkey@rbht.nhs.uk.
authors.forename: M I
authors.initials: MI
authors.lastname: Polkey
mesh_terms: D000818:Animals; D005260:Female; D005966:Glucuronidase / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000503:physiopathology; D052097:Quadriceps Muscle / Q000378:metabolism / Q000503:physiopathology; D012044:Regression Analysis; D012907:Smoking / Q000009:adverse effects / Q000097:blood / Q000378:metabolism*; D013147:Spirometry
chemical_list: D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: COPD; Klotho; Regeneration; Skeletal muscle; Smoking