Sarcopenia, a loss of muscle mass and function, is a common feature of aging which is associated with oxidative damage and apoptosis. Autophagy, a process for degradation of unnecessary cellular constituents, is considered to be a mechanism to combat muscle cell damage and death. We recently found that Drosophila Sestrin is an endogenous suppressor of the age-related muscle degeneration. Sestrins form a family of stress-inducible proteins that have antioxidant, AMPK-activating, TOR-inhibiting and autophagy- inducing functions. Mammals have three Sestrins (Sesn1-3), while Drosophila has a single Sestrin homologue (dSesn). In Drosophila, dSesn expression is highly enriched in skeletal muscles. dSesn-null mutant flies exhibit accelerated age-related skeletal and cardiac muscle degeneration that is preceded by accumulation of dysfunctional mitochondria, ubiquitinated protein aggregates and reactive oxygen species (ROS), all caused by defective autophagy. Conversely, muscle-specific overexpression of dSesn in aged flies enhances intramuscular autophagy, prevents age-dependent mobility decline and increases fatigue tolerance. These results suggest that Sestrin is an important homeostatic regulator of muscle physiology that promotes autophagy and attenuates age-associated myopathies. However, in order to overcome the physiological differences between insects and mammals, we need to develop and utilize mammalian animal models to investigate the role of Sestrins in age-associated muscle pathologies. Among the three Sestrins in mammals, Sesn1 is most highly expressed in skeletal and cardiac muscles. Interestingly, the expression of Sesn1 is downregulated in degenerating muscles of human patients. Reduced Sesn1 expression is also observed in atrophying mouse muscle in response to obesity or inactivity. Reintroduction of Sesn1 through adeno-associated viral vector into the degenerating mouse muscle partially restores the functional decline. Therefore, here we propose to generate and characterize the Sesn1-knockout mice to investigate more about endogenous Sesn1, which is expected to have critical myoprotective functions. Through this model, we will evaluate the role of Sesn1 in skeletal muscles in (i) preserving structural integrity and muscle functionality (mobility output) and (ii) maintaining insulin sensitivity (metabolic output) during normal aging. The proposed experiments will clarify if Sesn1 in mammals indeed is essential for the prevention of age- associated muscle degeneration and metabolic derangements, similar to dSesn in Drosophila cardiac and indirect flight muscle. In addition to being served as a relevant animal model for assessing Sesn1 function, the Sesn1-knockout mice can be also used as a valuable model of facilitated muscle aging. As Sesn1 is generally downregulated during muscle pathology in humans, supplementing Sesn1 activity through viral or pharmacological means may offer innovative rejuvenation methods for degenerating muscle in elderly population.
Metabolic anomalies, structural disintegration and wasting of muscle tissues are frequently observed in an elderly individual, and they set the clinical stage for diabetes, cardiovascular diseases and fall risks which are conditions with great public health significance. Therefore, interventions that can preserve muscle function at advanced ages are thus of substantial importance, and identification of cost-effective therapies that can preserve independence and healthy mobile capacity in the elderly would thus have a cumulative effect, influencing many other aspects of mental and physical health in a wide population demographic. Here we propose to investigate whether a protein named Sestrin1, which is a natural inhibitor of diverse age-associated diseases downregulated during muscle degeneration, is a new molecular target that can be used to preserve muscle function and quality of life in later ages.
|Ro, Seung-Hyun; Semple, Ian A; Park, Haewon et al. (2014) Sestrin2 promotes Unc-51-like kinase 1 mediated phosphorylation of p62/sequestosome-1. FEBS J 281:3816-27|
|Lee, Jun Hee; Budanov, Andrei V; Karin, Michael (2013) Sestrins orchestrate cellular metabolism to attenuate aging. Cell Metab 18:792-801|