Cardiac mass and cardiomyocyte size are governed by different genetic loci on either autosomes or chromosome Y in recombinant inbred mice.

Left ventricular hypertrophy is one of the main risk factors for cardiovascular mortality and morbidity. It has been proposed that hypertrophic stimuli act in great part by increasing the size of cardiomyocytes, and that the latter characteristic is a necessary condition to differentiate left ventricular hypertrophy from other benign forms of cardiac enlargement. To test whether the same genetic loci control the size of cardiomyocytes and left ventricular mass, we performed whole genome linkage analyses in a panel of 24 recombinant inbred AXB/BXA mouse strains. Whereas one major locus was linked to left ventricular mass in both males and females, loci linked to the size of cardiomyocytes were clearly distinct and showed sex-specific linkage. Moreover, the parental origin of chromosome Y had strong effects on the size of cardiomyocytes in male mice but did not affect left ventricular mass. In addition to showing that genetic loci that increase the size of cardiomyocytes are not necessarily linked to increased left ventricular mass, our findings have important consequences in evaluating cardiac phenotypes when performing genetic manipulations in mice, and in determining the cause of sex-specific differences when using models derived from C57BL/6J mice.

Ventilatory behavior during sleep among A/J and C57BL/6J mouse strains.

The pattern of breathing during sleep could be a heritable trait. Our intent was to test this genetic hypothesis in inbred mouse strains known to vary in breathing patterns during wakefulness (Han F, Subramanian S, Dick TE, Dreshaj IA, and Strohl KP. J Appl Physiol 91: 1962-1970, 2001; Han F, Subramanian S, Price ER, Nadeau J, and Strohl KP, J Appl Physiol 92: 1133-1140, 2002) to determine whether such differences persisted into non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Measures assessed in C57BL/6J (B6; Jackson Laboratory) and two A/J strains (A/J Jackson and A/J Harlan) included ventilatory behavior [respiratory frequency, tidal volume, minute ventilation, mean inspiratory flow, and duty cycle (inspiratory time/total breath time)], and metabolism, as performed by the plethsmography method with animals instrumented to record EEG, electromyogram, and heart rate. In all strains, there were reductions in minute ventilation and CO2 production in NREM compared with wakefulness (P < 0.001) and a further reduction in REM compared with NREM (P < 0.001), but no state-by-stain interactions. Frequency showed strain (P < 0.0001) and state-by-strain interactions (P < 0.0001). The A/J Jackson did not change frequency in REM vs. NREM [141 +/- 15 (SD) vs. 139 +/- 14 breaths/min; P = 0.92], whereas, in the A/J Harlan, it was lower in REM vs. NREM (168 +/- 14 vs. 179 +/- 12 breaths/min; P = 0.0005), and, in the B6, it was higher in REM vs. NREM (209 +/- 12 vs. 188 +/- 13 breaths/min; P < 0.0001). Heart rate exhibited strain (P = 0.003), state (P < 0.0001), and state-by-strain interaction (P = 0.017) and was lower in NREM sleep in the A/J Harlan (P = 0.035) and B6 (P < 0.0001). We conclude that genetic background affects features of breathing during NREM and REM sleep, despite broad changes in state, metabolism, and heart rate.

Interstrain variation in murine aerobic capacity.

PURPOSE: The contribution of genetic factors to aerobic capacity is unknown. The purpose of this study was to measure maximal aerobic performance among inbred strains of mice to provide basic heritability estimates. METHODS: Eight female mice, 8 to 10 wk old, in 10 inbred strains (A/J, AKR/J, Balb/cJ, C(3)H/HeJ, C57Bl/6J, C57L/J, C(3)Heb/FeJ, CBA/J, DBA/2J, and SWR/J) were run on a treadmill until exhaustion. The protocol started at 22 m.min(-1) and increased in speed approximately 6 m.min(-1) every 4 min. After 4 min at 42.4 m.min(-1), the grade was increased 2% every 4 min thereafter until the mouse could not run off of the shock grid (150 V; 1.5 mA). RESULTS: There were significant differences between inbred strains in maximal duration of exercise accomplished (P < 0.0001). The order of strain-specific exercise duration was Balb/cJ > SWR/J > CBA/J > C57L/J > C3H/HeJ > C3Heb/FeJ > C57Bl/6J > AKR/J > DBA/2J > A/J. Two measures of heritability in the broad sense, intraclass correlation (0.73), and the coefficient of genetic determination (0.58) were both significant. CONCLUSION: These data indicate that there is a strong genetic contribution to aerobic capacity in mice.

The A/J mouse lung as a model for developing new chemointervention strategies.

The use of the A/J mouse lung as a model for developing new chemo-intervention strategies was investigated by first inducing lung tumors with a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Lungs were then staged for tumor development and intervention therapy was initiated 42 weeks after carcinogen treatment. At this time point, an average of 7 pulmonary lesions were present on a standard histological section and the relative frequency of lesions was distributed as alveolar hyperplasias (38%), adenomas (40%), and adenocarcinomas (22%). Mice were treated for 4 or 8 weeks with cis-platinum alone or in combination with either indomethacin, an inhibitor of prostaglandin synthesis, metoclopramide, an inducer of poly(ADP) ribosylation, or nifedipine, a calcium channel blocker. The effect of indomethacin, metoclopramide, and nifedipine on tumor growth was also determined. The most dramatic effects were observed in lungs from mice treated for 8 weeks. cis-Platinum treatment caused a 37% reduction in the size of carcinomas, while tumor mass was reduced by 50 to 60% with cis-platinum in combination with metoclopramide and/or indomethacin. The inclusion of indomethacin therapy in conjunction with cis-platinum significantly enhanced the effectiveness of cis-platinum for inhibiting the growth of adenocarcinomas. In contrast, nifedipine appeared to ameliorate any of the inhibitory growth effects seen with cis-platinum treatment. Although none of the therapeutic combinations affected the size of adenomas, morphological differences were observed among treatment groups. A moderate to marked decrease in cytoplasm was observed in adenomas from mice treated with cis-platinum in combination with indomethacin or metoclopramide, cis-platinum plus metoclopramide and indomethacin, or metoclopramide plus indomethacin. Taken together, the results from these studies demonstrate that the A/J mouse lung can be used as a model to study the effectiveness of new intervention therapies for controlling malignant tumor growth. This model should also be applicable for studying the effectiveness of cancer prevention therapies on the progression of pulmonary hyperplasia.

Life table analysis and pathologic observations in male mice of a long-lived hybrid strain (Af X C57BL/6)F1.

We have utilized a long-lived (Af X C57BL/6)F1 hybrid strain of mice for a variety of aging studies. In this report we have characterized the life expectancy and pattern of spontaneous deaths in 202 mice, malignant and nonmalignant lesions in 64 male mice dying spontaneously, and organ weights and lesions in 39 male mice killed at selected ages. The maximum age observed was 41.5 months. The principal causes of death were malignant lymphoma and alveologenic neoplasms, which were present in 56.3% and 45.3%, respectively, of the mice dying spontaneously. A variety of other neoplastic and non-neoplastic lesions that are not infrequently seen in older mice were observed in these mice. Neoplasms seen in these mice that are rare in other mice included disseminated mast cell tumors in two mice and gastric adenocarcinoma in one mouse. In comparing the diseases observed in this hybrid strain with those reported for the parent strains, there was an incidence of malignant lymphoma similar to the C57BL/6 parent, an incidence of alveologenic neoplasms intermediate between the parent strains, and a markedly reduced incidence of amyloidosis. This study provides a detailed background of baseline hematologic and morphologic data in a long-lived hybrid of two commonly used strains of mice.

The effect of aging on the induction of experimental autoimmune thyroiditis.

The effect of age on the ability to elicit the various immune functions comprising experimental autoimmune thyroiditis in mice has been examined. Compared with young mice (2 to 3 mo), CBA/CaJ and A/J aged mice (20 to 30 mo) show a drastic reduction in their ability to develop circulating antibody after injection of mouse thyroglobulin (MTg) or mouse thyroid extract (MTE) in complete Freund's adjuvant (CFA). Delayed-type hypersensitivity responses were also depressed, as well as the ability of aged lymph node cells to proliferate in vitro to antigen and the ability of aged splenic T cells to function as helper cells for in vitro antibody production. However, after injection of these thyroid antigens in CFA, aged mice developed thyroid lesions either comparable to or only slightly less intense than those observed in young mice. The disparity between the levels of immune responses and thyroid lesions observed in aged mice can be explained by the greater susceptibility of aged thyroids to tissue damage, since transfer of identical numbers of Con A-activated MTE-primed young splenocytes to young and aged recipients results in a more severe thyroiditis in the aged recipients. Priming mice to MTE in CFA at 9 mo of age, at which time mice are responsive to MTE, did not enhance either T or B cell responsiveness to injection of MTE in CFA at 24 mo of age. Lymphocytes from MTE-injected aged mice also failed to transfer thyroiditis to young recipients after in vitro activation of the lymphocytes with Con A.

Lymphocyte aging in allophenic mice.

Allophenic mice are chimeras which are produced from the aggregation of two genotypically distinct embryos. In this study, embryos from the C57BL/6J and A/J strains were used to produce C57BL/6J----A/J allophenic mice. These strains were chosen because of their markedly different lifespans, their different glucose phosphate isomerase (GPI) isozymes, and their different H-2 haplotypes [C57BL/6J: long-lived, Gpi-1b, H-2b; A/J: short-lived, Gpi-1a, H-2a]. The mice were bled at two month intervals and the composition of their peripheral blood lymphocytes determined at each point from analysis of GPI isozymes and H-2 antigens. It was found that the proportion of long-lived (C57BL/6J) lymphocytes tended to increase with age. Moreover, the total lifespan of the allophenic mice was directly related to the percentage of long-lived lymphocytes in their peripheral blood.

Age-related auditory loss and genetics: an electrocochleographic comparison of six inbred strains of mice.

A genetic baseline was established for age-related auditory loss in the laboratory mouse (Mus musculus). Auditory nerve isoelectric thresholds were obtained in young, middle aged, and elderly mice at frequencies from 2 to 64 kHz. Six inbred strains of diverse genetic origin and widely varying life spans (298 to 774 days) were examined. Each strain displayed an age-related loss similar to that most often seen in the aging human (i.e., high-frequency losses occurred earliest, followed by losses of middle, and then of lower frequencies). The ranking of these strains in terms of the best to the poorest cochlear function in old age is as follows: SJL/J, AU/SsJ, AKR/J, A/J, C57BR/cdJ, and LP/J. Males and females were equally affected by the aging process.

Susceptibility of various strains of mice to urethan-induced lung tumors and depressed natural killer cell activity.

Inbred A/J, CBA/J, and C57BL/6 mice at age 7-8 weeks were inoculated with 1 mg urethan/g body weight. Three months later, 13.2, 1.8, and 0.1 tumors per lung were found in these mice, respectively. Cytotoxicity by spleen cells of normal and urethan-treated mice was analyzed in a 4-hour 51Cr release assay against YAC-1 cells. During the first 2 weeks after treatment, urethan strongly suppressed the cytotoxicity by spleen cells of A/J mice but had relatively little effect on the reactivity of spleen cells of CBA/J mice. Natural killer (NK) activity was not suppressed in urethan-treated C57BL/6 mice. The effect of urethan on natural in vivo antitumor resistance in the lungs was studied by measurement of elimination from the lungs of [125I]-deoxyuridine-labeled YAC-1 cells. Urethan caused profound and sustained suppression of in vivo NK reactivity in the lungs of A/J mice, had only a transient effect on CBA/J mice, and had no detectable effect on C57BL/6 mice. The differences in the effects of urethan on the natural antitumor resistance in the three strains of mice could not be attributed to a generally greater susceptibility of A/J mice to inhibition of NK activity, since cyclophosphamide (0.15 mg/g) equally suppressed the clearance from the lungs of the radiolabeled tumor cells in A/J, CBA/J, and C57BL/6 mice. These results indicate a positive correlation between susceptibility of A/J, CBA/J, and C57BL/6 mice to urethan-induced lung carcinogenesis and inhibition of in vitro and in vivo natural cell-mediated cytotoxicities and support the hypothesis that NK cells play a role in resistance to urethan-induced lung carcinogenesis.

Paternal effects on the development of social behavior in Mus musculus.

In order to extend the determination and description of effects of the father's phenotype on the development of social behavior in male mice, we tested 24 males from each of 2 highly inbred strains of Mus musculus, A/J and C57BL/6J. Approximately 1 week before the birth of the subjects, we replaced natural fathers with a foster parent such that, within each strain, 8 subjects had preweaning experience with same-strain males, 8 with other-strain males, and 8 with same-strain females, in addition to their natural mothers. Observations of social behavior were conducted at 21, 50, and 60 days of age. The results showed effects of the foster parent's phenotype on the development of social exploration in both strains and, possibly, on agonistic behavior in C57BL/6J mice. The different effects in the 2 strains indicate mechanisms dependent on genotype.

A relationship between hexobarbitone sleeping time and susceptibility to mescaline in mice from different strains.

Males from the following strains were surveyed with respect to their hexobarbitone sleeping time: A2G, C57BR, C3H, F/st, CBA, ICFW and Schneider. Males from the same strains had previously been surveyed with respect to the inhibitory effect of mescaline on their emotional defaecation. There is a strong interstrain correlation between the 2 measures. This correlation was unexpected on theoretical grounds and may have important pharmacogenetic implications.