The Cutting Edge: The Role of mTOR Signaling in Laminopathies.
The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that regulates anabolic and catabolic processes, in response to environmental inputs. The existence of mTOR in numerous cell compartments explains its specific ability to sense stress, execute growth signals, and regulate autophagy. mTOR signaling deregulation is closely related to aging and age-related disorders, among which progeroid laminopathies represent genetically characterized clinical entities with well-defined phenotypes. These diseases are caused by LMNA mutations and feature altered bone turnover, metabolic dysregulation, and mild to severe segmental progeria. Different LMNA mutations cause muscular, adipose tissue and nerve pathologies in the absence of major systemic involvement. This review explores recent advances on mTOR involvement in progeroid and tissue-specific laminopathies. Indeed, hyper-activation of protein kinase B (AKT)/mTOR signaling has been demonstrated in muscular laminopathies, and rescue of mTOR-regulated pathways increases lifespan in animal models of Emery-Dreifuss muscular dystrophy. Further, rapamycin, the best known mTOR inhibitor, has been used to elicit autophagy and degradation of mutated lamin A or progerin in progeroid cells. This review focuses on mTOR-dependent pathogenetic events identified in Emery-Dreifuss muscular dystrophy, LMNA-related cardiomyopathies, Hutchinson-Gilford Progeria, mandibuloacral dysplasia, and type 2 familial partial lipodystrophy. Pharmacological application of mTOR inhibitors in view of therapeutic strategies is also discussed.
['Chiarini|Francesca|F|', 'Evangelisti|Camilla|C|', 'Cenni|Vittoria|V|0000-0001-8062-1840', 'Fazio|Antonietta|A|', 'Paganelli|Francesca|F|', 'Martelli|Alberto M|AM|0000-0001-5196-7260', 'Lattanzi|Giovanna|G|0000-0002-7103-8722']
D000818:Animals D006801:Humans D034882:Lamins D008954:Models, Biological D009136:Muscular Dystrophies D015398:Signal Transduction D058570:TOR Serine-Threonine Kinases
mTOR laminopathies autophagy ageing metabolism Emery-Dreifuss muscular dystrophy (EDMD) Hutchinson-Gilford progeria syndrome (HGPS) bone remodeling cellular signaling lamin A/C