Elevated LDL-C, high blood pressure, and low peak V O2 associate with platelet mitochondria function in children -the Arkansas Active Kids study

Authors: DIAZ, EVA - University Arkansas For Medical Sciences (UAMS); ADAMS, SEAN - University Of California, Davis; WEBER, JUDITH - University Arkansas For Medical Sciences (UAMS); COTTER, MATTHEW - Arkansas Children'S Hospital; BORSHEIM, ELISABET - University Arkansas For Medical Sciences (UAMS)

Submitted to: Frontiers in Molecular Biosciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/7/2023
Publication Date: 3/22/2023
Citation: Diaz, E.C., Adams, S.H., Weber, J.L., Cotter, M., Borsheim, E. 2023. Elevated LDL-C, high blood pressure, and low peak V O2 associate with platelet mitochondria function in children -the Arkansas Active Kids study. Frontiers in Molecular Biosciences. 10:1136975. https://doi.org/10.3389/fmolb.2023.1136975.
DOI: https://doi.org/10.3389/fmolb.2023.1136975

Interpretive Summary: Platelets are blood cells and play a critical role in the occurrence of stroke and heart attacks (ischemic events). In the last 20 years strong evidence has shown that platelets also contribute to the initiation and progression of atherosclerosis disease. Platelets lack a nucleus which is the part of the cells that contains the genetic material and controls cell responses. It has been proposed that in the absence of a nucleus, platelet health is largely dependent on the health of their mitochondria (the powerhouse of cells). The implication is that platelet mitochondria could be used as target to improve platelet physiology and health outcomes. However, human data in this area is very limited. To address this limitation, we evaluated the association of platelet mitochondrial function with markers of cardiovascular health in children ages 7 to 10 years old. We found that high blood pressure and body fat increase the rate at which platelets consume oxygen (platelet mitochondria respiration). On the other hand, having elevated LDL cholesterol (bad cholesterol) and low fitness (aerobic capacity) decrease the ability of platelets to increase oxygen consumption and produce energy when demands are high. Taken together our results indicate that platelet mitochondria of children is affected by traditional cardiovascular disease risk factors. Future studies are urgently needed to assess if improving platelet mitochondria function in children could delay the onset and decrease the rates at which atherosclerosis and vascular dysfunction occur.

Technical Abstract: Context: Preclinical studies suggest that platelet mitochondria may serve as target to improve cardiovascular health outcomes, but human data are scarce. Objective: To evaluate the association of platelet mitochondria respiration with markers of cardiovascular health in children ages 7 to 10 years. Methods: Platelet mitochondria respiration (n = 91) was assessed by high-resolution respirometry (HRR): Routine (R) respiration, complex (C) I linked respiration, and maximal uncoupled electron transport capacity of CII (ECII) were measured. The respiratory control ratio (RCR) was calculated as maximal oxidative phosphorylation capacity of CI vs. leak (PCI/LCI). Peak V'O2 (incremental bike test) and body composition (dual-energy X-ray absorptiometry) were measured. Multiple generalized linear regression analysis was used to model the association of measures by HRR with variables of interest: adiposity, lipid status (normal vs. elevated: LDL-C, triglycerides), HOMA2-IR, high blood pressure (HBP), and demographics. Results: R and CI-linked respiration directly associated with adiposity, HBP, and peak VO2. R and CI-linked respiration negatively associated with elevated LDL-C and age. ECII positively associated with elevated LDL-C (log-ß = 0.54, p = 0.0100). HBP and peak V'O2 interacted in relation to RCR (log-ß = -0.01, p = 0.0278). Specifically, RCR was lowest among children with HBP and low aerobic capacity. HOMA2-IR did not associate with measures of platelet mitochondria respiration. Conclusion: Platelet CI mitochondria respiratory capacity increases in relation to adiposity and HBP which may reflect the ability of mitochondria to adapt to higher ATP demands. Elevated LDL-C is associated with lower platelet mitochondria respiratory capacity of CI which is compensated by CII. Substrate utilization is decreased in children with poor peak V'O2 and HBP.