Differentially co-expressed myofibre transcripts associated with abnormal myofibre proportion in chronic obstructive pulmonary disease.

BACKGROUND: Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD. METHODS: Forty-six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre-type distribution and cross-sectional area via immunofluorescence microscopy and RNA-sequenced to generate transcriptome-wide gene expression data. Sex-stratified k-means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co-expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype. RESULTS: Abnormal myofibre proportion was defined in males with COPD (n = 29) as <18% type I and/or >22% type IIx/IIax fibres and in females with COPD (n = 17) as <36% type I and/or >12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0 kg, P = 0.022), 6-min walk distance (300 vs. 353 m, P = 0.039) and forced expiratory volume in 1 s-to-forced vital capacity ratio (0.42 vs. 0.48, P = 0.041) compared with participants with COPD and normal myofibre proportions. Twenty-nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co-expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co-expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density. CONCLUSIONS: Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co-expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.

Interaction effect of systemic inflammation and modifiable rheumatoid cachexia risk factors on resting energy expenditure in patients with rheumatoid arthritis.

Background: In rheumatoid cachexia (RC), high resting energy expenditure (REE) is associated with loss of muscle mass driven by proinflammatory cytokines. The objectives of this study were to investigate parameters associated with RC, and the interaction between systemic inflammation and modifiable risk factors for RC on REE. Methods: Thirty-five rheumatoid arthritis (RA) and nineteen non-RA controls comparable in age, sex, race and BMI underwent measures of REE by indirect calorimetry. Clinical, dietary, body composition and physical function data were collected. Homeostasis model assessment for insulin resistance (HOMA-IR) and serum interleukin-6 (IL-6) were used as parameters of IR and systemic inflammation, respectively. Regression models tested association between REE and dependent variables, including pre-specified interaction tests involving HOMA-IR and IL-6 and dietary intake of protein per weight (PPW) and IL-6. Results: RA subjects were mostly women (94%) and had a median age of 54 years (50.5, 70) and BMI of 30.5 kg/m2 (26.1, 36.9). We observed a significant interaction effect between PPW and serum IL-6 on REE among RA subjects in the multiple regression model among RA. The upper tertile of PPW demonstrated a significant negative correlation between REE and IL-6 (ß=-19.97, 95% CI [-35.41, -4.54], p=0.01). The lower tertile of PPW demonstrated a significant positive correlation between REE and IL-6 (ß=42.24, 95% CI [4.25, 80.23], p=0.03). Conclusions: While IR can lead to muscle catabolism, IR was not significantly associated with REE in RA individuals. Higher dietary protein intake could attenuate the effect of systemic inflammation on REE in RA patients.