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A low quadriceps slow-twitch (ST), oxidative (relative to fast-twitch) fiber proportion is prevalent in chronic diseases such Chronic Obstructive Pulmonary Disease (COPD) and is associated with exercise limitation and poor outcomes. Benefits of an increased ST fiber proportion are demonstrated in genetically modified animals. Pathway analysis of published data of differentially expressed genes in mouse ST and FT fibers, mining of our microarray data and a qPCR analysis of quadriceps specimens from COPD patients and controls were performed. ST markers were quantified in C2C12 myotubes with EGF-neutralizing antibody, EGFR inhibitor or an EGFR-silencing RNA added. A zebrafish egfra mutant was generated by genome editing and ST fibers counted. EGF signaling was (negatively) associated with the ST muscle phenotype in mice and humans, and muscle EGF transcript levels were raised in COPD. In C2C12 myotubes, EGFR inhibition/silencing increased ST, including mitochondrial, markers. In zebrafish, egfra depletion increased ST fibers and mitochondrial content. EGF is negatively associated with ST muscle phenotype in mice, healthy humans and COPD patients. EGFR blockade promotes the ST phenotype in myotubes and zebrafish embryos. EGF signaling suppresses the ST phenotype, therefore EGFR inhibitors may be potential treatments for COPD-related muscle ST fiber loss.

Skeletal muscle dysfunction is a frequent extra-pulmonary manifestation of Chronic Obstructive Pulmonary Disease (COPD) with implications for both quality of life and survival. The underlying biology nevertheless remains poorly understood. We measured global gene transcription in the quadriceps using Affymetrix HuGene1.1ST arrays in an unselected cohort of 79 stable COPD patients in secondary care and 16 healthy age- and gender-matched controls. We detected 1,826 transcripts showing COPD-related variation. Eighteen exhibited ≥2fold changes (SLC22A3, FAM184B, CDKN1A, FST, LINC01405, MUSK, PANX1, ANKRD1, C12orf75, MYH1, POSTN, FRZB, TNC, ACTC1, LINC00310, MYH3, MYBPH and AREG). Thirty-one transcripts possessed previous reported evidence of involvement in COPD through genome-wide association, including FAM13A. Network analysis revealed a substructure comprising 6 modules of co-expressed genes. We identified modules with mitochondrial and extracellular matrix features, of which IDH2, a central component of the mitochondrial antioxidant pathway, and ABI3BP, a proposed switch between proliferation and differentiation, represent hubs respectively. COPD is accompanied by coordinated patterns of transcription in the quadriceps involving the mitochondria and extracellular matrix and including genes previously implicated in primary disease processes.

The Class II genes of the MHC represent a major locus with quantified effects on atopic (allergic) phenotypes in many studies of westernized Caucasians. Although asthma is considered a disease of western societies, typical components of the asthma phenotype, such as elevations of the IgE, are seen with parasitic infestation. We have therefore investigated the effects of the HLA-DRB1 locus on asthma and its intermediate phenotypes in Aboriginal people from the Kimberly region of Australia who were suffering from endemic hookworm infection. Recognizable correlates of allergic asthma were present in the subjects, including skin test positivity to house dust mite (HDM), specific IgE responses to HDM, and the total serum IgE. HLA-DRB1 alleles did not predict the presence of asthma, but multi-allelic tests of association showed the locus accounted for approximately 33% of the variance of the total serum IgE concentration and 17% of the variance of the specific IgE titres to HDM. Genetic admixture was excluded as a cause of the results. These effects of the MHC on IgE levels were an order of magnitude greater than that seen in Caucasians, consistent with the hypothesis that the genetic predisposition to allergic disease may be driven by adaptation to helminth infection. The results further suggest that parasitism per se is not protective against asthma.