Vitamin D and Skeletal Muscle Function in Chronic Obstructive Pulmonary Disease: Clinical Associations, Molecular Mechanisms and Genetic Influences

Abstract

This thesis investigates the role that serum 25(OH)D and serum 1,25(OH)2D concentration play in skeletal muscle dysfunction in patients with Chronic Obstructive Pulmonary Disease (COPD) with reference to clinical impact, potential molecular mechanisms and genetic influences. In a large cohort of COPD patients, neither serum 25(OH)D or serum 1,25()H)2D concentration were found to be associated with any volitional or non-volitional measures of peripheral or respiratory muscle strength. In a group of age and sex matched healthy control subjects serum 1,25()H)2D concentration was associated with muscle strength measures even after correction for potential confounding factors. Vitamin D status was not associated with quadriceps endurance in either COPD or control subjects when measured by repetitive magnetic stimulation. A sub-set of patients underwent a quadriceps muscle biopsy and mRNA levels of muscle fibre type and myogenic regulatory factors were measured. Serum 25(OH)D concentration was associated with MyHCIIa mRNA expression in control, but not COPD, subjects. Myf5 mRNA expression was strongly associated with MHC1 mRNA expression whilst mrf4 mRNA expression was strongly associated with MyHCIIa mRNA expression in control, but not COPD, subjects. Genotyping for all subjects included in the study was carried out for certain polymorphisms that were chosen because they have previously been reported to have an influence on the renin-angiotensin system in normal subjects, and may thus have an influence on skeletal muscle strength, or were already associated with muscle strength. In combination, the ACE I/D polymorphism, the AGT Met235Thr and the ATR1 A1166C polymorphisms had a significant influence on muscle strength in the COPD group. In normal subjects, the ACE I/D polymorphism was significantly associated with serum 25(OH)D concentration, and this association was stronger after correcting for confounding factors.