A comparative study of mitochondrial respiration in circulating blood cells and skeletal muscle fibers in women

Authors: ROSE, SHANNON - University Arkansas For Medical Sciences (UAMS); CARVALHO, EUGENIA - University Arkansas For Medical Sciences (UAMS); DIAZ, EVA - University Arkansas For Medical Sciences (UAMS); COTTER, MATTHEW - Arkansas Children'S Hospital; BENNURI, SIRISH - University Arkansas For Medical Sciences (UAMS); AZHAR, GOHAR - University Arkansas For Medical Sciences (UAMS); FRYE, RICHARD - University Of Arizona; Ferruzzi, Mario; BORSHEIM, ELISABET - University Arkansas For Medical Sciences (UAMS)

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/12/2019
Publication Date: 8/26/2019
Citation: Rose, S., Carvalho, E., Diaz, E.C., Cotter, M., Bennuri, S.C., Azhar, G., Frye, R.E., Adams, S.H., Borsheim, E. 2019. A comparative study of mitochondrial respiration in circulating blood cells and skeletal muscle fibers in women. American Journal of Physiology - Endocrinology and Metabolism. 317(3):E503-E512. https://doi.org/10.1152/ajpendo.00084.2019.
DOI: https://doi.org/10.1152/ajpendo.00084.2019

Interpretive Summary: Mitochondria are often described as the powerhouses of the cells, using oxygen to convert food energy to ATP (adenosine triphosphate which is the energy currency in the body). Skeletal muscle mitochondrial function is thought to be altered in unhealthy individuals (e.g., those with pre-diabetes); however, obtaining a muscle sample is a complicated procedure, limiting the study of muscle mitochondria in vulnerable populations, such as children and pregnant women. It has recently been suggested that the mitochondrial function in blood cells reflects the mitochondria function in muscle, and therefore can be used as a marker when it's difficult to obtain muscle biopsies. However, mitochondrial function in blood cells has never been compared to mitochondrial function in muscle in the same individuals. Therefore, in this study we collected both blood samples and muscle biopsies from 32 young women with a range of body weight (some were normal weight, some were overweight/obese). From blood samples, we isolated peripheral blood mononuclear cells (PBMCs) and platelets. We studied the samples using specialized equipment to determine how the mitochondria responded in their respiration (i.e., their usage of oxygen) to addition of various substrates (“fuel”) and inhibitors of various mitochondria components. When we compared mitochondrial respiration in circulating PBMCs, platelets and muscle samples from the same individual, we did not find a significant correlation. The data do however suggest a few qualitative similarities between mitochondrial function in platelets and muscle. We concluded that a blood sample cannot replace a muscle sample in studies of muscle mitochondrial function. However, it may still be that mitochondria in circulating cells can provide useful information about overall health status (including a reflection of all the body tissues) in certain populations including children.

Technical Abstract: Skeletal muscle mitochondrial respiration is thought to be altered in obesity, insulin resistance and type 2 diabetes; however, the invasive nature of tissue biopsies is an important limiting factor for studying mitochondrial function. Recent findings suggest that bioenergetics profiling of circulating cells may inform on mitochondrial function in other tissues in lieu of biopsies. Thus, we sought to determine whether mitochondrial respiration in circulating cells (peripheral blood mononuclear cells [PBMCs] and platelets) reflects that of skeletal muscle fibers derived from the same subjects. PBMCs, platelets and skeletal muscle (vastus lateralis) samples were obtained from 32 young (25-35 years) women of varying BMIs. Using high-resolution respirometry, mitochondrial respiration was measured in permeabilized cells and permeabilized muscle fibers, and extracellular flux analysis was used to measure mitochondrial respiration in intact cells. Direct raw measures of substrate [pyruvate, malate glutamate, (NADH-substrates) and succinate, (FADH2-substrate)]-driven respiration did not correlate between permeabilized muscle (per mg tissue) and permeabilized PBMCs or platelets (per 106 cells). However, OXPHOS coupling efficiency and electron transfer coupling efficiency of permeabilized platelets correlated with that of muscle (Spearman's p = 0.72; p = 0.009; Spearman's p = 0.45; p = 0.038, respectively). Respiratory parameters between intact and permeabilized cells were not positively correlated. Our data indicate that bioenergetics phenotypes in circulating cells cannot recapitulate all aspects of muscle mitochondrial function. Select circulating cell bioenergetics phenotypes possibly inform on overall metabolic health, but this postulate awaits further validation in cohorts spanning a larger range of insulin resistance and type 2 diabetes status.