Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise

Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity

Anti-Transforming Growth Factor ß Antibody Treatment Rescues Bone Loss and Prevents Breast Cancer Metastasis to Bone

Breast cancer often metastasizes to bone causing osteolytic bone resorption which releases active TGFβ. Because TGFβ favors progression of breast cancer metastasis to bone, we hypothesized that treatment using anti-TGFβ antibody may reduce tumor burden and rescue tumor-associated bone loss in metastatic breast cancer. In this study we have tested the efficacy of an anti-TGFβ antibody 1D11 preventing breast cancer bone metastasis. We have used two preclinical breast cancer bone metastasis models, in which either human breast cancer cells or murine mammary tumor cells were injected in host mice via left cardiac ventricle. Using several in vivo, in vitro and ex vivo assays, we have demonstrated that anti-TGFβ antibody treatment have significantly reduced tumor burden in the bone along with a statistically significant threefold reduction in osteolytic lesion number and tenfold reduction in osteolytic lesion area. A decrease in osteoclast numbers (p = 0.027) in vivo and osteoclastogenesis ex vivo were also observed. Most importantly, in tumor-bearing mice, anti-TGFβ treatment resulted in a twofold increase in bone volume (p<0.01). In addition, treatment with anti-TGFβ antibody increased the mineral-to-collagen ratio in vivo, a reflection of improved tissue level properties. Moreover, anti-TGFβ antibody directly increased mineralized matrix formation in calverial osteoblast (p = 0.005), suggesting a direct beneficial role of anti-TGFβ antibody treatment on osteoblasts. Data presented here demonstrate that anti-TGFβ treatment may offer a novel therapeutic option for tumor-induced bone disease and has the dual potential for simultaneously decreasing tumor burden and rescue bone loss in breast cancer to bone metastases. This approach of intervention has the potential to reduce skeletal related events (SREs) in breast cancer survivors

Les Isoformes intestinales et hépatiques des "fatty acid binding proteins" dans le trafic intracellulaire des acides gras et leur expression dans un modèle animal de syndrome métabolique

La consommation excessive de graisses est aujourd hui l une des causes principales de l augmentation de la prévalence des maladies métaboliques. Après leur hydrolyse, les graisses sont absorbées par les entérocytes sous forme d acides gras (AG) et de monoglycérides qui sont pris en charge dans la cellule par de petites protéines cytosoliques, les FABPs. L entérocyte exprime la I- FABP et la L-FABP dont la fonction spécifique dans le trafic intracellulaire des AG est toujours mal connue. Pour appréhender les relations structure-fonction in vivo, la caractérisation immunocytochimique de cellules Cos-1 transfectées exprimant de grandes quantités de FABPs a été réalisée. Ces protéines ciblent l AG vers des sites de métabolisation (mitochondries ou réticulum endoplasmique / appareil de Golgi). Lorsque chaque protéine est exprimée isolément dans la cellule, elle distribue de façon spécifique un analogue fluorescent d AG, suggérant une fonction propre pour chacune. Mais lorsqu elles sont toutes deux présentes, elles coopèrent pour la distribution de l AG dans des régions comparables à celles ciblées par la seule I-FABP suggérant un rôle de sensor pour cette protéine. Ce travail a été poursuivi en montrant que les régulations de l expression de la I-FABP et de la L-FABP différaient dans un modèle de syndrome métabolique induit par un régime riche en fructose chez le rat. Dans ce modèle, nous avons aussi analysé les effets de l apport dans le régime des AG polyinsaturés oméga 3 sur l expression de gènes impliqués dans le métabolisme énergétique et l inflammation. Un rôle spécifique de PPAR delta dans le foie et le cœur a pu être mis en évidence.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Effects of omega-3 fatty acids on gene expression in the fructose fed rat, a model of metabolic syndrome

National audienc

Beneficial effects of omega-3 fatty acids on the consequences of a fructose diet are not mediated by PPAR delta or PGC1 alpha

Purpose To study, in high-fructose-fed rats, the effect of a dietary enrichment in omega-3 polyunsaturated fatty acids (n-3 PUFA) on the expression of genes involved in lipid metabolism and cardiovascular function. Methods Twenty-eight male ''Wistar Han'' rats received for 8 weeks, either a standard chow food or an isocaloric 67 % fructose diet enriched or not in alpha-linolenic acid (ALA) or in docosahexaenoic (DHA) and eicosapentaenoic acids (EPA) mix (DHA/EPA). After sacrifice, blood was withdrawn for biochemical analyses; heart, periepididymal adipose tissue and liver were collected and analyzed for the expression of 22 genes by real-time PCR. Results Fructose intake resulted in an increase in liver weight and triglyceride content, plasma triglyceride and cholesterol concentrations, although no difference in glu- cose and insulin. In the liver, lipogenesis was promoted as illustrated by an increase in stearoyl-CoA desaturase and fatty acid synthase (Fasn) together with a decrease in PPAR gamma, delta and PPAR gamma coactivator 1 alpha (PGC1 alpha) expression. In the heart, Fasn and PPAR delta expression were increased. The addition of ALA or DHA/EPA into the diet resulted in a protection against fructose effects except for the decreased expression of PPARs in the liver that was not counterbalanced by n-3 PUFA suggesting that n-3 PUFA and fructose act inde- pendently on the expression of PPARs and PGC1 alpha. Conclusions In liver, but not in heart, the fructose-enri- ched diet induces an early tissue-specific reduction in PPAR gamma and delta expression, which is insensitive to n-3 PUFA intake and dissociated from lipogenesis

HoSAGE: sarcopenia in older patient with intermediate / high-risk prostate cancer, prevalence and incidence after androgen deprivation therapy: study protocol for a cohort trial

International audienceAbstract Background Sarcopenia is defined by a loss of muscle strength associated to a decrease in skeletal muscle mass. Ageing greatly contributes to sarcopenia as may many other factors such as cancer or androgen deprivation therapies (ADT). This cohort study aims to evaluate (1) the prevalence of muscle disorders and sarcopenia in older patients before initiation of intermediate to high risk prostate cancer treatment with ADT and radiotherapy, and (2) the occurrence and/or aggravation of muscle disorders and sarcopenia at the end of cancer treatment. Methods This cohort study is monocentric and prospective. The primary objectives are to determine the risk factor of sarcopenia prevalence and to study the relationship between ADT and sarcopenia incidence, in patients 70 years and older with histologically proven localized or locally advanced prostate cancer, addressed to a geriatrician (G8 score ≤14) for comprehensive geriatric assessment (CGA) in Marseille University Hospital. Secondary objectives encompass, measurement of sarcopenia clinical criteria along prostate oncological treatment; evaluation of the quality of life of patients with sarcopenia; evaluation of the impact of socio-behavioral and anthropological factors on sarcopenia evolution and incidence; finally the evaluation of the impact of ADT exposure on sarcopenia. Sarcopenia prevalence was estimated to be between 20 and 30%, therefore the study will enroll 200 patients. Discussion The current guidelines for older patients with prostate cancer recommend a pelvic radiotherapy treatment associated to variable duration (6 to 36 months) of ADT. However ADT impacts muscle mass and could exacerbate the risks of sarcopenia. Our study intends to assess the specific effect of ADT on sarcopenia incidence and/or worsening as well as to estimate sarcopenia prevalence in this population. The results of this cohort trial will lead to a better understanding of sarcopenia prevalence and incidence necessary to further elaborate a prevention plan. Trial registration The protocol was registered to the French drug and device regulation agency under the number 2019-A02319-48, before beginning the study (11/12/2019). The ClinicalTrials.gov identifier is NCT04484246, registration on the ClinicalTrials.gov ( https://clinicaltrials.gov/ct2/show/NCT04484246 )

Histological and Urodynamic Effects of Autologous Stromal Vascular Fraction Extracted from Fat Tissue with Minimal Ex Vivo Manipulation in a Porcine Model of Intrinsic Sphincter Deficiency

International audienceTo evaluate the healing abilities of autologous stem cell therapy (stromal vascular fraction) prepared from adipose tissue we used an automated system without an ex vivo culture phase in a pig model of intrinsic sphincteric deficiency.A total of 15 pigs underwent endoscopic section of the urethral sphincter. Animals were then randomly assigned to 3 groups, including 1) controls without stromal vascular fraction injection, 2) early injection with stromal vascular fraction 2 to 3 days after section and 3) late stromal vascular fraction injection delivery 30 days after injury. Extraction and stromal vascular fraction injection were performed as a single procedure. The stromal vascular fraction was characterized by flow cytometry. Mesenchymal stem cell-like cells were enumerated by clonogenicity (cfu fibroblast) assay. Study end points included histological assessment of the urethral injury surface and urodynamics to determine maximum urethral pressure.Flow cytometry analysis revealed a mesenchymal stem cell-like phenotype in a mean ± SD of 47.3% ± 11.8% of stromal vascular fraction cells. The cfu fibroblast frequency was 1.3 to 6.6/100 stromal vascular fraction cells (1.3% to 6.6%). Stromal vascular fraction injection was associated with a reduction of the urethral injury surface in the early and late injection groups compared with the respective controls (7% vs 17% and 1% vs 13%, p = 0.050 and 0.029, respectively). On day 30 after injection maximum urethral pressure was significantly higher in the injected groups than in the control group, that is 64% vs 50% of maximum urethral pressure on day 0 (p = 0.04).These data demonstrate the ability of an autologous stromal vascular fraction to improve the urethral healing process in a large animal model of intrinsic sphincteric deficiency

Histological and Urodynamic Effects of Autologous Stromal Vascular Fraction Extracted from Fat Tissue with Minimal Ex Vivo Manipulation in a Porcine Model of Intrinsic Sphincter Deficiency

International audienceTo evaluate the healing abilities of autologous stem cell therapy (stromal vascular fraction) prepared from adipose tissue we used an automated system without an ex vivo culture phase in a pig model of intrinsic sphincteric deficiency.A total of 15 pigs underwent endoscopic section of the urethral sphincter. Animals were then randomly assigned to 3 groups, including 1) controls without stromal vascular fraction injection, 2) early injection with stromal vascular fraction 2 to 3 days after section and 3) late stromal vascular fraction injection delivery 30 days after injury. Extraction and stromal vascular fraction injection were performed as a single procedure. The stromal vascular fraction was characterized by flow cytometry. Mesenchymal stem cell-like cells were enumerated by clonogenicity (cfu fibroblast) assay. Study end points included histological assessment of the urethral injury surface and urodynamics to determine maximum urethral pressure.Flow cytometry analysis revealed a mesenchymal stem cell-like phenotype in a mean ± SD of 47.3% ± 11.8% of stromal vascular fraction cells. The cfu fibroblast frequency was 1.3 to 6.6/100 stromal vascular fraction cells (1.3% to 6.6%). Stromal vascular fraction injection was associated with a reduction of the urethral injury surface in the early and late injection groups compared with the respective controls (7% vs 17% and 1% vs 13%, p = 0.050 and 0.029, respectively). On day 30 after injection maximum urethral pressure was significantly higher in the injected groups than in the control group, that is 64% vs 50% of maximum urethral pressure on day 0 (p = 0.04).These data demonstrate the ability of an autologous stromal vascular fraction to improve the urethral healing process in a large animal model of intrinsic sphincteric deficiency