Personalized preventive medicine: genetics and the response to regular exercise in preventive interventions

Abstract

Regular exercise and a physically active lifestyle have favorable effects on health. Several issues related to this theme are addressed in this report. A comment on the requirements of personalized exercise medicine and in-depth biological profiling along with the opportunities that they offer is presented. This is followed by a brief overview of the evidence for the contributions of genetic differences to the ability to benefit from regular exercise. Subsequently, studies showing that mutations in TP53 influence exercise capacity in mice and humans are succinctly described. The evidence for effects of exercise on endothelial function in health and disease also is covered. Finally, changes in cardiac and skeletal muscle in response to exercise and their implications for patients with cardiac disease are summarized. Innovative research strategies are needed to define the molecular mechanisms involved in adaptation to exercise and to translate them into useful clinical and public health applications.

Keywords: Endothelium; Genetics; Individual differences; Mitochondria; Personalized medicine.

Figure 1

(A) Mechanisms and in vivo effects of tumor protein 53 (p53) regulation of mitochondrial function. p53 can regulate mitochondrial function through both its nuclear transcriptional target genes (such as SCO2, TFAM, FDXR, AIF, and p53R2 [RRM2B]) and its various post-translational interactions with proteins found inside the mitochondria (such as TFAM, POLG, and SSB). p53 can translocate into the mitochondria utilizing the disulfide relay system that depends on respiration and CHCHD4 and by binding to RECQL4 which has a mitochondrial targeting sequence. p53 promotes mitochondrial biogenesis activities such as respiratory complex I and IV assembly via AIF and SCO2, respectively, and ATP synthase formation. Mitochondrial genomic DNA (mtDNA) maintenance and repair can be mediated by the physical interaction of p53 with proteins found in the matrix such as TFAM, POLG, and SSB. These activities of p53 are likely to function in concert with a host of other factors to determine human exercise capacity. (B) The presence of p53 in p53+/+ versus p53−/− mice had a marked effect in improving the respiratory exchange ratio (RER, a marker of aerobic metabolic capacity) during treadmill running after exercise training. This phenomenon observed in p53−/− mice (null state with no p53 expression) should be distinguished from that in mice expressing mutated p53, such as in the Li-Fraumeni syndrome (LFS) mouse model. (C) Skeletal muscle mitochondrial function can be noninvasively assessed in vivo using P-31 magnetic resonance spectroscopy (³¹P-MRS). The recovery kinetics of phosphocreatine (PCr) levels in skeletal muscle after exercise-induced depletion can serve as an indicator of mitochondrial oxidative phosphorylation capacity. PCr recovery was faster in individuals carrying LFS mutations (LFS TP53) compared to noncarrier and healthy volunteer subjects (Controls). AIF = apoptosis-inducing factor 1; CHCHD4 = mitochondrial intermembrane space import and assembly protein 40; FDXR = NADPH:adrenodoxin oxidoreductase, mitochondrial; p53R2 = p53-inducible ribonucleotide reductase small subunit 2 homolog; POLG = DNA polymerase subunit gamma-1; RECQL4 = ATP-dependent DNA helicase Q4; SCO2 = cytochrome oxidase deficient homolog 2; SSB = lupus La protein; TFAM = transcription factor A, mitochondrial;

Figure 2

Exercise training effects on cardiac muscle in HF. SERCA2 = sarcoplasmic reticulum Ca2+ ATPase; phospho-Ser(16)-PLN = phospho-Ser16-phospholamban; phospho-Thr(17)-PLN = phospho-Thr17-phospholamban; NCX = Na+/Ca2+ exchanger; PP1 = phosphatase 1; NFAT = nuclear factor of activated T-cells.

Figure 3

Exercise training effects on skeletal muscle in HF. TNF-α = tumor necrosis factor− α; IL−6 = interleukin−6; IL−1β = interleukin−1β; and IGF−1 = insulin-like growth factor−1.