Effects of limiting energy availability via diet and physical activity on mammalian target of rapamycin-related signaling in rat mammary carcinomas.

This study evaluated how different approaches to limiting energy availability (LEA) by 15% affected mammalian target of rapamycin (mTOR)-related signaling in mammary carcinomas. Female Sprague Dawley rats, injected with 50mg 1-methyl-1-nitrosourea per kilogram body weight, were randomized to a control or three LEA interventions: (i) sedentary and restricted rats fed to 85% of energy available to the control or motorized wheel running (37 m/min) for an average of (ii) 1621 ± 55 (WRL) or (iii) 3094 ± 126 (WRH) meters/day with food intake adjusted to provide the same net amount of available energy across LEA interventions. Under these conditions, LEA reduced overall cancer burden by 28% (P = 0.04) and down-regulated mTOR-related signaling (Hotelling multivariate, P = 0.002). Among the regulatory nodes assessed, reduced levels of activated protein kinase B (pAkt) and induction of sirtuin 1 (SIRT1) were the most influential factors in distinguishing between sham control and LEA carcinomas. P-Akt was predictive of observed changes in levels of proteins involved in cell cycle control (r = 0.698, P < 0.0001) and induction of apoptosis (r = -0.429, P = 0.014). Plasma insulin and leptin were strongly associated with carcinoma pAkt levels. Consistent with downregulation of mTOR-related signaling by LEA, evidence of decreased lipid synthesis in carcinomas was observed (Hotelling multivariate, P < 0.001) and was negatively correlated with SIRT1 induction. Despite large differences between control and LEA, effects on mTOR regulation were insufficient to distinguish among LEA intervention groups. Given the modest effects observed on the LKB1/AMP-activated protein kinase regulatory node, NADH and NADPH rather than ATP may be more limiting for tumor growth when LEA is 15%.