RESUMEN
The signaling mechanisms that mediate the important effects of contraction to increase glucose transport in skeletal muscle are not well understood, but are known to occur through an insulin-independent mechanism. Muscle-specific knockout of LKB1, an upstream kinase for AMPK and AMPK-related protein kinases, significantly inhibited contraction-stimulated glucose transport. This finding, in conjunction with previous studies of ablated AMPKalpha2 activity showing no effect on contraction-stimulated glucose transport, suggests that one or more AMPK-related protein kinases are important for this process. Muscle contraction increased sucrose nonfermenting AMPK-related kinase (SNARK) activity, an effect blunted in the muscle-specific LKB1 knockout mice. Expression of a mutant SNARK in mouse tibialis anterior muscle impaired contraction-stimulated, but not insulin-stimulated, glucose transport. Whole-body SNARK heterozygotic knockout mice also had impaired contraction-stimulated glucose transport in skeletal muscle, and knockdown of SNARK in C2C12 muscle cells impaired sorbitol-stimulated glucose transport. SNARK is activated by muscle contraction and is a unique mediator of contraction-stimulated glucose transport in skeletal muscle.
Asunto(s)
Glucosa/metabolismo , Contracción Muscular/fisiología , Músculo Esquelético/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP , Adulto , Animales , Transporte Biológico/efectos de los fármacos , Western Blotting , Línea Celular , Activación Enzimática , Ejercicio Físico/fisiología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Técnicas In Vitro , Insulina/farmacología , Masculino , Ratones , Ratones Noqueados , Mioblastos/citología , Mioblastos/efectos de los fármacos , Mioblastos/metabolismo , Fosforilación , Condicionamiento Físico Animal/fisiología , Proteínas Serina-Treonina Quinasas/genética , Interferencia de ARN , Sorbitol/farmacologíaRESUMEN
BACKGROUND: Exercise is a modifiable factor that is inversely related to risk for breast cancer. To determine if physical activity has a preventative effect on development of premalignant breast lesions, we examined the association between exercise and the incidence of proliferative benign breast disease. METHODS: In 1997, the Nurses' Health Study II cohort reported levels of physical activity during adolescence and adulthood using a validated recall instrument. We followed 40,318 participants free from benign breast disease (BBD) or cancer prospectively for four years and confirmed 232 proliferative benign breast lesions by centralized pathology review. Cox proportional hazards models estimated the age-adjusted and multivariable-adjusted relative risks for physical activity and proliferative benign breast disease. RESULTS: We observed a significant inverse association for walking and incidence of BBD, risk was reduced by 9% per hour of walking (95% CI 0% to 17%), (p trend = 0.05). Despite a small number of cases, risk of columnar cell lesions also suggested an inverse association with strenuous activity (RR for 4 or more hours of strenuous activity per week = 0.62; 0.31-1.22 compared to < 1 h per week). CONCLUSIONS: This study suggests that exercise may be inversely associated with the risk of developing proliferative benign breast disease, one of the earliest steps in the development of breast cancer.