Aging Influences Cardiac Mitochondrial Gene Expression and Cardiovascular Function following Hemorrhage Injury

Abstract

Cardiac dysfunction and mortality associated with trauma and sepsis increase with age. Mitochondria play a critical role in the energy demand of cardiac muscles, and thereby on the function of the heart. Specific molecular pathways responsible for mitochondrial functional alterations after injury in relation to aging are largely unknown. To further investigate this, 6-and 22-monthold rats were subjected to trauma-hemorrhage (T-H) or sham operation and euthanized following resuscitation. Left ventricular tissue was profiled using our custom rodent mitochondrial gene chip (RoMitochip). Our experiments demonstrated a declined left ventricular performance and decreased alteration in mitochondrial gene expression with age following T-H and we have identified c-Myc, a pleotropic transcription factor, to be the most upregulated gene in 6-and 22-month-old rats after T-H. Following T-H, while 142 probe sets were altered significantly (39 up and 103 down) in 6-month-old rats, only 66 were altered (30 up and 36 down) in 22-month-old rats; 36 probe sets (11 up and 25 down) showed the same trend in both groups. The expression of c-Myc and cardiac death promoting gene Bnip3 were increased, and Pgc1-α and Ppar-α a decreased following T-H. Eleven tRNA transcripts on mtDNA were upregulated following T-H in the aged animals, compared with the sham group. Our observations suggest a cmyc-regulated mitochondrial dysfunction following T-H injury and marked decrease in age-dependent changes in the transcriptional profile of mitochondrial genes following T-H, possibly indicating cellular senescence. To our knowledge, this is the first report on mitochondrial gene expression profile following T-H in relation to aging.

Mitochondrial function in hypoxic ischemic injury and influence of aging

“…In order to study nuclear-mitochondria cross talk, our laboratory developed a mitochondrial gene chip with probe sets representing the transcriptome of the genes on the mitochondria and that of the nucleus important for the structure and function of mitochondria, together called the mitoscriptome (Raju et al , 2011). We found significant upregulation of genes involved in glycolytic pathways in cardiomyocytes subjected to hypoxia demonstrating a shift in energy production from mitochondria to glycolysis (Jian et al , 2011b). Recently it has been found that humanin, a mitochondria derived peptide, exhibits strong cytoprotective actions against various stress and disease models and suggested to be part of a retrograde signaling that involves nuclear-mitochondria crosstalk (Gong et al , 2014).…”

“…c-MYC appears to act via increasing transcription factor A mitochondrial (TFAM) and is critically important in hypoxia/ischemia. In a mitochondrial gene expression profiling of a rat model of hemorrhagic shock in our laboratory, c-MYC exhibited most change following the injury (Jian et al , 2011b). …”

“…ERRα increases nuclear respiratory factor 2 (NRF2), which regulates the cell cycle, cell differentiation, and mitochondrial biogenesis (Scarpulla, 2008). PGC-1α has also been noted to have effects on energy production and defense systems against ROS (Jian et al , 2011b). PGC-1α activity is modulated by nutrient availability, calcium, ROS, insulin, thyroid hormone, estrogens, hypoxia, ATP demand, cytokines, and c-MYC (Puigserver and Spiegelman, 2003).…”

“…A number of genes related to cellular energetics are altered with age following trauma-hemorrhage based on an analysis with a custom-made rodent mitochondrial gene chip (RoMitochip) in 6 and 22 month old rats (Jian et al , 2011b). Aged rats had a decline in the number and amplitude of expression of mitochondria-related genes compared to the younger rats following trauma-hemorrhage.…”

Influence of aging and hemorrhage injury on Sirt1 expression: Possible role of myc-Sirt1 regulation in mitochondrial function

“…However the mechanisms by which aging adversely affect injury outcome are not fully elucidated. In the injury model, trauma-hemorrhage (T-H), we have recently demonstrated increased endoplasmic reticulum stress, decreased left ventricular performance and decreased mitochondrial function [8–10]. Hemorrhagic shock causes a whole body hypoxia/reoxygenation injury, leading to dysregulation of biochemical pathways and multiple organ dysfunction syndrome [11–17].…”