Low plasma lysophosphatidylcholines are associated with impaired mitochondrial oxidative capacity in adults in the Baltimore Longitudinal Study of Aging

Abstract

The decrease in skeletal muscle mitochondrial oxidative capacity with age adversely affects muscle strength and physical performance. Factors that are associated with this decrease have not been well characterized. Low plasma lysophosphatidylcholines (LPC), a major class of systemic bioactive lipids, are predictive of aging phenotypes such as cognitive impairment and decline of gait speed in older adults. Therefore, we tested the hypothesis that low plasma LPC are associated with impaired skeletal muscle mitochondrial oxidative capacity. Skeletal muscle mitochondrial oxidative capacity was measured using in vivo phosphorus magnetic resonance spectroscopy (³¹ P-MRS) in 385 participants (256 women, 129 men), aged 24-97 years (mean 72.5) in the Baltimore Longitudinal Study of Aging. Postexercise recovery rate of phosphocreatine (PCr), k_PCr , was used as a biomarker of mitochondrial oxidative capacity. Plasma LPC were measured using liquid chromatography-tandem mass spectrometry. Adults in the highest quartile of k_PCr had higher plasma LPC 16:0 (p = 0.04), 16:1 (p = 0.004), 17:0 (p = 0.01), 18:1 (p = 0.0002), 18:2 (p = 0.002), and 20:3 (p = 0.0007), but not 18:0 (p = 0.07), 20:4 (p = 0.09) compared with those in the lower three quartiles in multivariable linear regression models adjusting for age, sex, and height. Multiple machine-learning algorithms showed an area under the receiver operating characteristic curve of 0.638 (95% confidence interval, 0.554, 0.723) comparing six LPC in adults in the lower three quartiles of k_PCr with the highest quartile. Low plasma LPC are associated with impaired mitochondrial oxidative capacity in adults.

Keywords: aging; lysophosphatidylcholine; metabolomics; mitochondria; skeletal muscle.

Figure 1

Chemical structure of lysophosphatidylcholine molecular species with fatty acid group noted on the right column. LPCs consist of a glycerol backbone, a phosphate head group at the sn‐3 position, a choline (C₅H₁₄NO), and a single fatty acid chain at the sn‐1 or sn‐2 position. The LPC shown have fatty acids that vary from 16 to 20 carbons in length with the number of double bonds ranging from 0 to 4. The sn‐1 isomer is shown here for simplicity. LPC 20:3 and 20:4 isomers are not distinguished by this LC‐MS/MS assay

Figure 2

Cross‐validated receiver operating curves of the relationship of the 6 significant plasma LPC species with the highest quartile of k _PCr using Super Learner, cross‐validated (CV) Super Learner, and eight machine‐learning algorithms. BAGGed CART, bootstrap aggregated classification and regression tree; CV, cross‐validated; LASSO, least absolute shrinkage and selection operator; GBM, generalized boosted regression; GLM, generalized linear model (i.e., main effects logistic regression); MARS, multivariate adaptive regression splines

Figure 3

Synthesis pathway of cardiolipin from lysophosphatidylcholine and lysophosphatidic acid. AGPAT, acylglycerol‐3‐phosphate acyltransferase; ATX, autotaxin; CLS1, cardiolipin synthase; CDP, cytidine diphosphate; CDS, CDP‐diacylglycerol synthase; CMP, cytidine monophosphate; CTP, cytidine triphosphate; EL, endothelial lipase; GPAT, glycerol‐3‐phosphate acyltransferase; LCAT, phosphatidylcholine‐sterol acyltransferase; PTPMT1, phosphatidylglycerophosphate and protein‐tyrosine phosphatase 1; PGP synthase, phosphatidylglycerophosphate synthase; PLA₂, phospholipase A₂; PP_i, pyrophosphate; TAZ, tafazzin