Serum Acylglyceride Metabolites are Negatively Associated with Muscle Oxidative Capacity, but Not with Physical Activity, in Severe COPD

Abstract

RATIONALEChronic obstructive pulmonary disease (COPD) is associated with altered metabolism and body composition that accompany worse outcomes. Serum lipid metabolites are dysregulated in COPD (e.g. sphingolipids, polyunsaturated fatty acids, ceramides). Loss of skeletal muscle mitochondrial oxidative capacity is implicated in mediating the association between hyperlipidemia and COPD. As both oxidative capacity and physical activity are negatively associated with COPD severity, this study aimed to determine whether lipid dysregulation in COPD was associated with muscle oxidative capacity and/or physical inactivity. We hypothesized that alteration of lipid metabolites in COPD would be associated with muscle oxidative capacity, independent of pulmonary function.METHODSCurrent and former smokers with COPD (n=44, FEV1=61±4%pred) and without COPD (CON) (n=63, FEV1=93±2%pred) volunteered. Untargeted prime and lipid metabolites were measured using liquid chromatography and mass spectrometry. Medial gastrocnemius oxidative capacity was assessed at rest from the recovery rate constant (k) of muscle oxygen consumption using near‐infrared spectroscopy. Daily step count and physical activity (average vector magnitude units (VMU)/min) were measured over 7 days by waist‐worn triaxial accelerometer.RESULTSThe k value (1.12±0.05 vs. 1.68±0.06 min−1, P<0.0001) and VMU/min (170±26 vs. 450±50 VMU/min, P=0.004) were lower in severe COPD (FEV1<50%pred, n=14–16) compared with CON. 129 prime metabolites and 470 lipids with known identity were quantified. Using sex as a covariate, lipidomics revealed that 24 lipids (19 sphingomeylins) were differentially expressed in COPD, consequent to a diminished sex difference of sphingomeylins in COPD (FDR<0.05). Total, and some individual, fatty acid concentrations were greater in severe COPD than in CON (FDR<0.05). After adjusting for FEV1%pred, we observed that grouped diacylglyceride (DG; Spearman’s rho = −0.745, FDR=0.03) and triacylglyceride (TG; rho = −0.811, FDR=0.01) were negatively associated with muscle oxidative capacity, but not physical activity, in severe COPD.DISCUSSIONWe found 24 lipids, including 19 sphingomyelins, increased in COPD with sex as covariant; and that sex‐dependent differences in sphingomyelin in CON were diminished COPD. This may contribute to more rapid progression of COPD in women than in men. Strong negative associations between blood lipids and muscle oxidative capacity, but not physical activity, suggest that impaired mitochondrial function may play a role in the accumulation of serum aclyglycerides in severe COPD. These data provide a strong rationale for targeting mitochondrial deficits by exercise training, or other means, to improve outcomes in COPD.Support or Funding InformationShenzhen Technology University (RL); VA MERT I01 BX00435, R01HL111437, R01HL129727 (TKH); Swiss National Science Foundation P300P3_151705 (AA); ATS‐2014‐03, Pulmonary Education and Research Foundation (HBR); R01HL089856; R01HL089897; UL1TR000124.