Reducing the burden of COPD by targeting skeletal muscle mass and function. Targets and endpoints for drug development

Chronic Obstructive Pulmonary disease (or emphysema and chronic bronchitis) is a family of lung diseases usually but not always caused by cigarette smoking. There is an urgent need to develop new drugs to treat this condition since existing therapies are insufficiently effective. Importantly in more advanced disease complications outside the lung become as important as the lung disease itself and in fact one of the most effective treatments, pulmonary rehabilitation (supervised exercise training) is thought to work in large part by improving the strength and function of the walking muscles; thus we believe a drug which could magnify or extend the benefit of this treatment would be every useful. Thus the aim of this work package is to bring together the groups interested this field in Great Britain with selected drug companies. Three stages of the WP are described. In the first we will assess what material is available and whether, by sharing, the consortium can achieve some ?quick wins? which will facilitate the development of drugs or ideas already known to the participants. In the second we will do some detailed studies which will relate actual rates of protein synthesis in the leg muscles to more readily accessible measures that can be obtained from blood or muscle since this will allow the latter measures to guide drug development more reliably. As part of this work we will also build the largest ever cohort of COPD patients from whom a muscle biopsy and clinical data are available. Lastly we will study patients around the time of rehabilitation (which improves muscle function) and acute exacerbation (which worsens it) to try to identify further targets for new drugs

The overall aim of this work package is to gain new information regarding the aetiology underlying loss of skeletal muscle function, since this has a clinically relevant impact on morbidity, mortality and healthcare utilisation in Chronic Obstructive Pulmonary Disease (COPD). Key components of the program include (a) quick wins by screening material from available cohorts to assist with development decisions for available products and the development of regulatory endpoints relevant to the non-pulmonary effects of the disease, (b) direct measurement of protein synthesis using labelled amino acids and (c) extension of existing cohorts both when stable and at times of changing muscle bulk (after rehabilitation and exacerbation). Novel clinical features of the cohort will be the assessment of quadriceps strength, bulk, field test of walking performance and the obtaining of paired muscle and blood samples.

Signalling pathways to be evaluated by the consortium will include (i) Muscle cell phenotype (MHC gene expression and fibre-type, mitochondrial function, myogenic transcription factors, such as myf5, myoD, myogenin, SRF, MRTFA/B and MASTR, and mechano-sensitive regulators of transcription factor activity specifically FHL1 and FHL3 (ii) Anabolic and insulin signalling (Akt,mTOR, P70s6 kinase, 4EBP1, FOXO1, IRS-1, IRS-2 and phospho-IRS-2 and GLUT-1/GLUT-4 expression (iii) Myostatin signalling (myostatin and extracellular regulators of myostatin (follistatin, FLRG and GASP-1) by ELISA (iv)Protein degradation (MAFbx, cathepsin-L and PDK2 (mRNA by qPCR, total and phospho, protein by Western blotting), (v) metabolism; Muscle metabolites (ATP, PCr, glycogen, lactate by fluorescence), muscle pyruvate dehydrogenase complex activity pyruvate dehydrogenase kinase 2 and 4 mRNA and (vi) cellular markers of ageing. Importantly material will be made available to pharma who have offered to share the cost of these analyses as an ?in-kind contribution.

Within the workpacakge a responsive management style will allow movement of funds so that the consortium as a whole can focus its funds to obtain maximum productivity and will have a steering committee co-chaired by academia and pharma. Externally the WP will interdigitate with WP 1,2 & 3 for maximum ?added-value? and more widely with the PRO-active and COPD Foundation initiatives with the aim of supporting regulatory approval for outcomes relevant to antisarcopenic drugs