RESUMEN
Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these age-related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1's activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3's phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to age-related muscle atrophy, and GDF signaling is a proposed mechanism.
Asunto(s)
Envejecimiento/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Estrés Oxidativo , Animales , Células Cultivadas , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteína 1 del Complejo de la Esclerosis Tuberosa/deficiencia , Proteína 1 del Complejo de la Esclerosis Tuberosa/metabolismoRESUMEN
Rapamycin, an inhibitor of mTOR kinase, increased median lifespan of genetically heterogeneous mice by 23% (males) to 26% (females) when tested at a dose threefold higher than that used in our previous studies; maximal longevity was also increased in both sexes. Rapamycin increased lifespan more in females than in males at each dose evaluated, perhaps reflecting sexual dimorphism in blood levels of this drug. Some of the endocrine and metabolic changes seen in diet-restricted mice are not seen in mice exposed to rapamycin, and the pattern of expression of hepatic genes involved in xenobiotic metabolism is also quite distinct in rapamycin-treated and diet-restricted mice, suggesting that these two interventions for extending mouse lifespan differ in many respects.
Asunto(s)
Longevidad/efectos de los fármacos , Sirolimus/farmacología , Factores de Edad , Animales , Restricción Calórica , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Factores Sexuales , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Rapamycin, a potent immunomodulatory drug, has shown promise in the amelioration of numerous age-associated diseases including cancer, Alzheimer's disease and cardiac hypertrophy. Yet the elderly, the population most likely to receive therapeutic rapamycin, are already at increased risk for infectious disease; thus concern exists that rapamycin may exacerbate age-associated immune dysfunctions and worsen infection outcomes. Herein, we examined the impact of enteric delivered rapamycin monotherapy (eRapa) on the susceptibility of aged (22-24month) C57BL/6 mice to Streptococcus pneumoniae, the leading bacterial cause of community-acquired pneumonia. Following challenge with S. pneumoniae, administration of eRapa conferred modest protection against mortality. Reduced mortality was the result of diminished lung damage rather than reduced bacterial burden. eRapa had no effect on basal levels of Interleukin (IL)-1α, IL-6, IL-10, IL-12p70, KC, Interferon-γ, Tumor necrosis factor α and Monocyte chemotactic protein-1 in whole lung homogenates or during pneumococcal pneumonia. Previously we have demonstrated that cellular senescence enhances permissiveness for bacterial pneumonia through increased expression of the bacterial ligands Laminin receptor (LR), Platelet-activating factor receptor (PAFr) and Cytokeratin 10 (K10). These proteins are co-opted by S. pneumoniae and other respiratory tract pathogens for host cell attachment during lung infection. UM-HET3 mice on eRapa had reduced lung cellular senescence as determined by levels of the senescence markers p21 and pRB, but not mH2A.1. Mice on eRapa also had marked reductions in PAFr, LR, and K10. We conclude that eRapa protected aged mice against pneumonia through reduced lung cellular senescence, which in turn, lowered bacterial ligand expression.