Date Published: February 04, 2019
Publisher: John Wiley and Sons Inc.
Author(s): Richard D. Semba, Pingbo Zhang, Fatemeh Adelnia, Kai Sun, Marta Gonzalez‐Freire, Norman Salem, Nicholas Brennan, Richard G. Spencer, Kenneth Fishbein, Mohammed Khadeer, Michelle Shardell, Ruin Moaddel, Luigi Ferrucci.
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 (31P‐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), kPCr, 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 kPCr 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 kPCr with the highest quartile. Low plasma LPC are associated with impaired mitochondrial oxidative capacity in adults.
Progressive mitochondrial dysfunction is an important hallmark of aging (López‐Otín, Blasco, Partridge, Serrano, & Kroemer, 2013). A variety of changes in mitochondria have been described in aging skeletal muscle, including a reduction of number, morphological changes, reduced oxidative phosphorylation efficiency that impairs ATP production, and excess release of reactive oxygen species that cause oxidative damage and possibly accumulation of mitochondrial DNA mutations (Gonzalez‐Freire et al., 2015; Kent & Fitzgerald, 2016). The decline of skeletal muscle mitochondrial oxidative capacity has been associated with lower gait speed, especially in task that require endurance (Choi et al., 2016). Higher physical activity has been associated with higher mitochondrial mass and function (Kent & Fitzgerald, 2016). Insulin resistance is associated with lower mitochondrial function, although the direction of this association is still a matter of discussion (Fabbri et al., 2017).
The characteristics of the study population by quartile of mitochondrial oxidative capacity (kPcr) are shown in Table 1. The mean (standard deviation) for kPCr was 0.020 (0.005). Adults with higher kPcr were significantly younger and taller and more likely to be male. There were no significant differences across quartiles of kPCr by weight or BMI. Aerobic capacity (VO2 max) was significantly higher in adults with higher kPCr. Eight LPC species were measured using liquid chromatography–tandem mass spectrometry (LC‐MS/MS). The chemical structures and fatty acid chains of the LPC species are shown in Figure 1. Mean plasma LPC concentrations by quartile of mitochondrial oxidative capacity are shown in Table 2. LPC 16:1, 17:0, 18:0, 18:1, 18:2, and 20:3 concentrations were significantly higher across quartiles of kPCr, adjusting for age, sex, and height. Adults in the highest quartile of mitochondrial oxidative capacity were also compared with the lower three quartiles combined (Table 3). Higher plasma LPC 16:0, 16:1, 17:0, 18:1, 18:2, and 20:3 concentrations were significantly associated with higher kPCr in multivariable linear regression model adjusting for age, sex, and height (p < 0.05). LPC 18:0 and 20:4 were higher in the highest quartile of mitochondrial oxidative capacity compared with the lower three quartiles in the models above, although differences were not statistically significant (p = 0.07, p = 0.09, respectively). In an alternative multivariate linear regression model adjusting for age and sex but not height, higher plasma LPC 16:1 (p = 0.005), 18:1 (p = 0.001), 18:2 (p = 0.008), and 20:3 (p = 0.001) were associated with higher kPCr,but plasma LPC 16:0, 17:0, 18:0, and 20:4 were not significantly associated with kPCr. Additional analyses were conducted using an interaction term between kPCr and sex added to the multivariable linear regression model described above to determine whether the relationship detected was between men and women. The p‐values for the interaction term (kPCr and sex) for the six different LPC species ranged between 0.19 and 0.98. The present study shows that higher plasma LPC with fatty acid chains 16:0 (palmitic acid), 16:1 (palmitoleic acid), 17:0 (margaric acid), 18:1 (oleic acid), 18:2 (linoleic acid), and 20:3 (eicosatrienoic acid, n‐3, dihomo‐gamma‐linolenic acid, n‐6, and/or mead acid, n‐9) are associated with higher mitochondrial oxidative capacity in adults. The major species of 20:3 and 20:4 are in the n‐6 configuration in plasma. To our knowledge, this is the first study to identify circulating biomarkers associated with mitochondrial oxidative capacity in skeletal muscle in humans. The authors declare no conflicts of interest. Source: http://doi.org/10.1111/acel.12915