The manifestations of ageing in the pathophysiology of skeletal muscle dysfunction in COPD
Creators: name: Patel, Mehul Sureshchandra
Publisher: name: Imperial College London
Year: 2014

description: The aim of this thesis was to address the impact of the skeletal muscle adaptations that occur in Chronic Obstructive Pulmonary Disease (COPD) and subsequently to identify tools that may be relevant in the management of patients with structural and functional muscle abnormalities. To establish whether the type I to II fibre shift that occurs in COPD is associated with mortality, a retrospective multicentre analysis of 392 stable COPD outpatients was performed. Across the whole cohort, fibre shift was an independent predictor of mortality in a model also including age and FEV1%predicted. In patients with GOLD stage III or IV disease, quadriceps strength, but not fibre shift had an independent association with an increased risk of mortality. Therapies targeting quadriceps fibre shift and weakness may be of therapeutic value; practical tools that identify relevant patients may have clinical utility. Since the pathophysiological adaptations that occur may be considered to be a manifestation of accelerated biological ageing, potentially relevant physical and biological markers of ageing were identified following a review of the literature. The Short Physical Performance Battery (SPPB) is used in gerontology to assess lower limb function, but its determinants have not been previously evaluated in COPD. SPPB score was measured in 109 stable COPD outpatients; 31 also had a quadriceps biopsy. Quadriceps strength and exercise capacity were the only independent predictors of SPPB score. Stratification by SPPB score identified patients with locomotor muscle atrophy and impairment in strength, exercise capacity and daily physical activity. Patients with a reduced SPPB score had a higher proportion of type II fibres. Subsequently, the SPPB potentially has practical utility in the assessment of COPD patients. Systemic Klotho and GDF-15 levels are associated with mortality in non-selected populations; these proteins were evaluated initially in the serum and then the skeletal muscle of healthy controls, smokers and COPD patients. Circulating Klotho levels were reduced in COPD and smokers, related to quadriceps strength and increased after successful smoking cessation. Serum GDF-15 levels were elevated in COPD, and related to a marker of systemic oxidative damage and locomotor muscle atrophy. Klotho and GDF-15 were expressed in skeletal muscle. Quadriceps GDF-15 expression was elevated in COPD patients as compared to controls and diaphragm expression. Klotho levels were reduced in the locomotor muscle of human smokers and smoke-exposed mice. Humans had relatively higher Klotho levels in respiratory muscle. Quadriceps Klotho levels positively correlated with local protein carbonylation and were also unexpectedly elevated in patients with established skeletal muscle dysfunction; immunohistochemistry confirmed that Klotho was associated with regenerating muscle fibres. Modulation of Klotho and GDF-15 signalling, and potentially other age-related molecules, may provide therapeutic options to COPD patients.