Inhibition of mTORC1 signaling in aged rats counteracts the decline in muscle mass and reverses multiple parameters of muscle signaling associated with sarcopenia

Abstract

12There is a lack of pharmacological interventions available for sarcopenia, a progressive age-13 associated loss of muscle mass, leading to a decline in mobility and quality of life. We found 14 mTORC1 (mammalian target of rapamycin complex 1), a well-established critical positive 15 modulator of mass, to be hyperactivated in sarcopenic muscle. Furthermore, inhibition of the 16 mTORC1 pathway counteracted sarcopenia as determined by observing an increase in muscle 17 mass and fiber type cross sectional area, surprising because mTORC1 signaling has been shown 18 to be required for muscle mass gains in some settings. Additionally, several genes related to 19 senescence were downregulated, while gene expression indicators of neuromuscular junction 20 denervation were diminished using a low dose of a rapalog. Therefore mTORC1 inhibition may 21 delay the progression of sarcopenia by directly and indirectly modulating multiple age-associated 22 pathways, implicating mTORC1 as a therapeutic target to treat sarcopenia. 23 29 decrease in walking speed is one of the strongest predictors of mortality in humans, and this 30 finding is associated with sarcopenia (3, 4). In addition to frailty and sarcopenia, aging of course 31 affects every tissue system and greatly increases susceptibility to other serious diseases and co-32 morbidities, such as cancer, heart failure, chronic kidney disease, loss of vision, dementia and 33 Alzheimer's disease (1, 5, 6). 34Experimental data strongly suggest the coordinated regulation of aging by distinct 35 molecular pathways (7); modulation of these pathways can counteract several age-related 36 diseases and co-morbidities, and prolong life (7-10). Of these signaling pathways, genetic or 37 pharmacological inhibition of the mammalian target of rapamycin (mTORC1) is thus far the 38 best-validated intervention to delay age-related pathophysiological changes (11). For instance, 39 the use of an mTORC1 inhibitor, rapamycin, even when administered at later stages in life, has 40 been shown to extend lifespan in mice (12)(13)(14)(15). Pharmalogical agents related to rapamycin are 41 called "rapalogs". Use of a rapalog for aging-like indications has recently been translated to 42 human beings, where it was shown to improve responses to vaccinations in the elderly, 43 coincident with decreasing signs of immune-senescence (16). The low dose rapalog treatment 44 used in the human study was reverse-translated to rats, where it was shown that intervention late 45 in life could prevent signs of age-related kidney pathology (17). However, there has always been 46 4 concern about the potential effects of rapamycin and rapalogs on skeletal muscle. For example, 47 inhibition of the mTORC1 pathway was shown to entirely block responses to compensatory 48 hypertrophy in mice (18). This certainly gave the impression that activation of mTORC1 49 signaling was desireable for the maintenance of muscle mass. Most recently it was shown that 50 rapamcyin treatment inhibited muscle mass increase caused by myostatin lo...

Native Whey Induces Similar Adaptation to Strength Training as Milk, despite Higher Levels of Leucine, in Elderly Individuals

“…Increasing age has been associated with greater basal mTORC-1 phosphorylation in both mice [45] and humans [46]. Recently, this age-related elevation of mTORC1 activity was linked to muscle fiber damage and loss in mice [47] and its inhibition by a rapalog (RAD001) showed protective effects against sarcopenia in rats [48]. Our findings suggest that resistance exercise may be capable of reducing or normalizing mTORC1 phosphorylation in aging individuals.…”