Cardiovascular Response to Beta-Adrenergic Blockade or Activation in 23 Inbred Mouse Strains

We report the characterisation of 27 cardiovascular-related traits in 23 inbred mouse strains. Mice were phenotyped either in response to chronic administration of a single dose of the β-adrenergic receptor blocker atenolol or under a low and a high dose of the β-agonist isoproterenol and compared to baseline condition. The robustness of our data is supported by high trait heritabilities (typically H2>0.7) and significant correlations of trait values measured in baseline condition with independent multistrain datasets of the Mouse Phenome Database. We then focused on the drug-, dose-, and strain-specific responses to β-stimulation and β-blockade of a selection of traits including heart rate, systolic blood pressure, cardiac weight indices, ECG parameters and body weight. Because of the wealth of data accumulated, we applied integrative analyses such as comprehensive bi-clustering to investigate the structure of the response across the different phenotypes, strains and experimental conditions. Information extracted from these analyses is discussed in terms of novelty and biological implications. For example, we observe that traits related to ventricular weight in most strains respond only to the high dose of isoproterenol, while heart rate and atrial weight are already affected by the low dose. Finally, we observe little concordance between strain similarity based on the phenotypes and genotypic relatedness computed from genomic SNP profiles. This indicates that cardiovascular phenotypes are unlikely to segregate according to global phylogeny, but rather be governed by smaller, local differences in the genetic architecture of the various strains

Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing.

Prolonged unaccustomed exercise involving muscle lengthening (eccentric) actions can result in ultrastructural muscle disruption, impaired excitation-contraction coupling, inflammation and muscle protein degradation. This process is associated with delayed onset muscle soreness and is referred to as exercise-induced muscle damage. Although a certain amount of muscle damage may be necessary for adaptation to occur, excessive damage or inadequate recovery from exercise-induced muscle damage can increase injury risk, particularly in older individuals, who experience more damage and require longer to recover from muscle damaging exercise than younger adults. Furthermore, it is apparent that inter-individual variation exists in the response to exercise-induced muscle damage, and there is evidence that genetic variability may play a key role. Although this area of research is in its infancy, certain gene variations, or polymorphisms have been associated with exercise-induced muscle damage (i.e. individuals with certain genotypes experience greater muscle damage, and require longer recovery, following strenuous exercise). These polymorphisms include ACTN3 (R577X, rs1815739), TNF (-308 G>A, rs1800629), IL6 (-174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A, rs680). Knowing how someone is likely to respond to a particular type of exercise could help coaches/practitioners individualise the exercise training of their athletes/patients, thus maximising recovery and adaptation, while reducing overload-associated injury risk. The purpose of this review is to provide a critical analysis of the literature concerning gene polymorphisms associated with exercise-induced muscle damage, both in young and older individuals, and to highlight the potential mechanisms underpinning these associations, thus providing a better understanding of exercise-induced muscle damage

Characterization of myocardium, isolated cardiomyocytes, and blood pressure in WKHA and WKY rats

We previously reported that the left ventricular (LV) mass of Wistar-Kyoto (WKY)-derived hyperactive (WKHA) rats was higher than that of WKY rats in the absence of a difference in systolic blood pressure. To extend these earlier observations, we conducted a series of functional and morphological investigations on both strains. Analysis of tissue sections revealed that the surface of ventricular tissue from WKHA rats was higher than that of WKY rats, without any enlargement of the cavity area. Analysis of isolated adult cells showed that cell width (as well as cell volume) of ventricular cardiomyocytes was significantly higher in WKHA than WKY rats. However, LV of WKHA rats contained approximately 33% less cardiomyocytes than those from WKY rats. Mean intracellular free calcium concentration of cardiomyocytes was also higher in WKHA than WKY rats. Hemodynamic measurements revealed that the values of the maximum rates of pressure change (dP/dt) were higher in LV from WKHA rats. However, these differences were reduced (-dP/dt) or abolished (+dP/dt) when the values were normalized for both the number and mean cross-sectional area of ventricular cardiomyocytes. Mean levels of systolic and diastolic blood pressure (corresponding to the 24-h average of measurements obtained continuously in conscious unrestrained animals using radiotelemetric implants) were not different between strains. However, circadian rhythm was more evident in WKY rats, because the difference between morning and night values of systolic and diastolic blood pressure was greater (by 3 mmHg) in WKY rats. Altogether, our data validate the use of WKHA rats as models of predominantly concentric LV hypertrophy developing in the absence of increased mean levels of hemodynamic cardiac load and show that the hypertrophy phenotype is more pronounced in isolated cardiomyocytes than at the level of the whole ventricle

Distinct QTLs are linked to cardiac left ventricular mass in a sex-specific manner in a normotensive inbred rat intercross

Genetic mapping of the progeny of an F2 intercross between WKY and WKHA rats had previously allowed us to detect male-specific linkage between locus Cm24 and left ventricular mass index (LVMI). By further expanding that analysis, we detected additional loci that were all linked to LVMI in a sexspecific manner despite their autosomal location. In males, we detected one additional locus (Lvm8) on Chromosome 5 (LOD = 3.4), the two loci Lvm13 (LOD = 4.5) and Lvm9 (LOD = 2.8) on Chromosome 17, and locus Lvm10 (LOD = 4.2) on Chromosome 12. The locus Lvm13 had the same boundaries as locus Cm26 previously reported by others using a different cross. None of these loci showed linkage to LVM in females. In contrast, we identified in females the novel locus Lvm11 on Chromosome 15 (LOD = 2.8) and locus Lvm12 (LOD = 2.7) that had the same boundaries on Chromosome 3 as locus Cm25 detected previously by others using a cross of other normotensive strains. In prepubertal males, there were no differences in the width of cardiomyocytes from WKY and WKHA rats, but cardiomyocytes from WKHA became progressively wider than that of WKY as sexual maturation progressed. Altogether, these results provide evidence that distinct genes may influence LVMI of rats in a sexdependent manner, maybe by involving sex-specific interactions of sex steroids with particular genes involved in the determination of LVMI and/or cardiomyocyte width.Bastien Llamas, Zhibin Jiang, Marie-Line Rainville, Sylvie Picard and Christian F. Descheppe