Life-long spontaneous exercise does not prolong lifespan but improves health span in mice

BackgroundLife expectancy at birth in the first world has increased from 35 years at the beginning of the 20th century to more than 80 years now. The increase in life expectancy has resulted in an increase in age-related diseases and larger numbers of frail and dependent people. The aim of our study was to determine whether life-long spontaneous aerobic exercise affects lifespan and healthspan in mice.ResultsMale C57Bl/6J mice, individually caged, were randomly assigned to one of two groups: sedentary (n = 72) or spontaneous wheel-runners (n = 72). We evaluated longevity and several health parameters including grip strength, motor coordination, exercise capacity (VO2max) and skeletal muscle mitochondrial biogenesis. We also measured the cortical levels of the brain-derived neurotrophic factor (BDNF), a neurotrophin associated with brain plasticity. In addition, we measured systemic oxidative stress (malondialdehyde and protein carbonyl plasma levels) and the expression and activity of two genes involved in antioxidant defense in the liver (that is, glutathione peroxidase (GPx) and manganese superoxide dismutase (Mn-SOD)). Genes that encode antioxidant enzymes are considered longevity genes because their over-expression may modulate lifespan. Aging was associated with an increase in oxidative stress biomarkers and in the activity of the antioxidant enzymes, GPx and Mn-SOD, in the liver in mice. Life-long spontaneous exercise did not prolong longevity but prevented several signs of frailty (that is, decrease in strength, endurance and motor coordination). This improvement was accompanied by a significant increase in the mitochondrial biogenesis in skeletal muscle and in the cortical BDNF levels.ConclusionLife-long spontaneous exercise does not prolong lifespan but improves healthspan in mice. Exercise is an intervention that delays age-associated frailty, enhances function and can be translated into the clinic

Effects of asymmetric dimethylarginine on renal arteries in portal hypertension and cirrhosis

AIM. To evaluate the effects of asymmetric dimethylarginine (ADMA) in renal arteries from portal hypertensive and cirrhotic rats. METHODS. Rat renal arteries from Sham (n = 15), pre-hepatic portal hypertension (PPVL; n = 15) and bile duct ligation and excision-induced cirrhosis (BDL; n = 15) were precontracted with norepinephrine, and additional contractions were induced with ADMA (10-6-10-3 mol/L), an endogenous inhibitor of nitric oxide (NO) synthase. Concentration-response curves to acetylcholine (1 × 10-9-3 × 10-6 mol/L) were determined in precontracted renal artery segments with norepinephrine in the absence and in the presence of ADMA. Kidneys were collected to determine the protein expression and activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catabolizes ADMA. RESULTS. In renal arteries precontracted with norepinephrine, ADMA caused endothelium-dependent contractions. The pD2 values to ADMA were similar in the Sham and PPVL groups (4.20 ± 0.08 and 4.11 ± 0.09, P > 0.05, respectively), but were lower than those of the BDL group (4.79 ± 0.16, P < 0.05). Acetylcholine-induced endothelium-dependent relaxation that did not differ, in terms of pD2 and maximal relaxation, among the 3 groups studied. Treatment with ADMA (3 × 10-4 mol/L) inhibited acetylcholine-induced relaxation in the 3 groups, but the inhibition was higher (P < 0.05) in the BDL group compared with that for the Sham and PPVL groups. The mRNA and protein expression of DDAH-1 were similar in kidneys from the three groups. Conversely, DDAH-2 expression was increased (P < 0.05) in PPVL and further enhanced (P < 0.05) in the BDL group. However, renal DDAH activity was significantly decreased in the BDL group. CONCLUSION. Cirrhosis increased the inhibitory effect of ADMA on basal- and induced-release of NO in renal arteries, and decreased DDAH activity in the kidney

Potenciación producida por la vasopresina de la respuesta constrictora adrenérgica en la arteria mesentérica de rata / Inmaculada Noguera Salvá ; directores Salvador Huch López, José M. Vila Salinas, Mª Carmen Martínez Martínez.

Tesis-Universidad de Murcia.Consulte la tesis en: BCA. GENERAL. ARCHIVO UNIVERSITARIO. T.M.-1345.Consulte la tesis en: BCA. GENERAL. Fac. Veterinaria. Sala de estudio. Tesis-V 82

Gene expression profile induced by ovariectomy in bone marrow of mice: a functional approach to identify new candidate genes associated to osteoporosis risk in women.

El objetivo fue identificar genes candidatos implicados en la fisiopatología de la osteoporosis, utilizando como modelo los ratones ovariectomizados (OVX) frente a ratones no ovariectomizados (SHAM). Se encontraron 180 genes con expresión génica diferencial y 23 rutas importantes entre las que destacaron la via de desarrollo de células B, la vía de señalización PI3K en células B y la via de de señalización FcgRIIb en células B. Se analizó la asociación a densidad mineral ósea (DMO) de polimorfismos (SNPs) en genes cuya expresión se incrementó (IL7R y CD79A) o disminuyó (GPX3 y IRAK3) por OVX en ratones en una cohorte de 706 mujeres posmenopáusicas. Se detectó asociación significativa del SNP rs8177447 en el gen GPX3 con DMO femoral y en los SNPs rs3810153 y rs1428922 del gen CD79A con DMO lumbar, resultados que refuerzan el papel de las vías de antioxidantes y de las células B en el metabolismo óseoOsteoporosis is a multifactorial skeletal pathology with a main genetic component. To date, however, the majority of genes associated with this pathology remain unknown since genes cataloged to date only explain a part of the heritability of bone phenotypes. In the present study, we have used a genome-wide gene expression approach by means of microarrays to identify new candidate genes involved in the physiopathology of osteoporosis, using as a model the ovariectomized (OVX) mice by comparing global bone marrow gene expression of the OVX mice with those of SHAM operated mice. One hundred and eighty transcripts were found to be differentially expressed between groups. The analysis showed 23 significant regulatory networks, of which the top five canonical pathways included B-cell development, primary immunodeficiency signaling, PI3K signaling in B-cells, phospholipase C signaling, and FcgRIIB signaling in B-cells. Twelve differentially expressed genes were validated by MALDI-TOF mass spectrometry with good reproducibility. Finally, the association to bone phenotypes of SNPs in genes whose expression was increased (IL7R and CD79A) or decreased (GPX3 and IRAK3) by OVX in mice was analyzed in a cohort of 706 postmenopausal women. We detected an association of a SNP in a gene involved in the detoxification of free radicals like glutathione peroxidase 3 (GPX3) with femoral neck BMD (rs8177447, P=0.043) and two SNPs in the Ig-alpha protein of the B-cell antigen component gene (CD79A) with lumbar spine BMD (rs3810153 and rs1428922, P=0.016 and P=0.001, respectively). These results reinforce the role of antioxidant pathways and of B-cells in bone metabolism. Furthermore, it shows that a genome-wide gene expression approach in animal models is a useful method for detecting genes associated to BMD and osteoporosis risk in humans