RESUMEN
SCOPE: The muscle loss during aging results from the blunt of protein synthesis and poses threat to the elderly health. This study aims to investigate whether betaine affects muscle loss by improving protein synthesis. METHODS AND RESULTS: Male C57BL/6J mice are raised from age 12 or 15 months. Mice are fed with AIN-93M diet without or with 2% w/v betaine in distilled water as control group or betaine intervention group (Bet), respectively. Betaine supplementation to mice demonstrates better body composition, grip strength, and motor function. Muscle morphology upregulates expression of myogenic regulate factors, and elevates myosin heavy chain and also improves in Bet group. Betaine promotes muscle protein synthesis via tethering mammalian target of rapamycin complex1 protein kinase (mTORC1) on the lysosomal membrane thereby activating mTORC1 signaling. All these effects aforementioned are time-dependent (p < 0.05). Ultrahigh-performance liquid chromatography results show that betaine increases S-adenosyl-l-methionine (SAM) via methionine cycle. SAM sensor-Samtor-overexpression in C2C12 cells could displace mTORC1 from lysosome thereby inhibiting the mTORC1 signaling. Addition of betaine attenuates this inhibition by increasing SAM level and then disrupting interaction of Samtor complex. CONCLUSIONS: These observations indicate that betaine could promisingly promote protein synthesis to delay age-related muscle loss.
Asunto(s)
Betaína/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Metiltransferasas/antagonistas & inhibidores , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , S-Adenosilmetionina/metabolismo , Envejecimiento/efectos de los fármacos , Envejecimiento/patología , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Membranas Intracelulares/efectos de los fármacos , Membranas Intracelulares/metabolismo , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Masculino , Metionina/metabolismo , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The dietary intakes of choline and betaine have been related to the mortality of some neoplasms, but their effects on hepatocellular carcinoma (HCC) mortality are still unknown. We examined the associations between dietary choline, five choline-containing compounds, different choline forms, betaine intake and HCC mortality. In total, 905 newly diagnosed HCC patients were enrolled in the Guangdong Liver Cancer Cohort study. Dietary intake was assessed by a valid food frequency questionnaire. Liver cancer-specific mortality (LCSM) and all-cause mortality (ACM) were calculated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by Cox proportional hazards models. It was found that a higher total choline intake was associated with lower ACM, Q4 vs. Q1: HR = 0.72, 95% CI: 0.53-0.97, Ptrend = 0.012 in the fully adjusted model. The associations between total choline intake and LCSM were not significant. Similar associations were found between water-soluble choline intake and HCC mortality, where the fully adjusted HR for ACM was 0.72, 95% CI: 0.53-0.98, Ptrend = 0.017. However, null associations were found between neither phosphatidylcholine (the most abundant lipid-soluble choline) nor total lipid-soluble choline intake and HCC mortality. These results implied that the favorable associations between the total choline intake and ACM were more attributed to water-soluble choline. Furthermore, no significant associations were observed between betaine intake and HCC mortality. Future human intervention trials regarding choline supplementation and liver disease recovery should take the forms into consideration rather than just the total amount alone.