PMID- 30781376 OWN - NLM STAT- MEDLINE DCOM- 20190531 LR - 20211204 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 20 IP - 4 DP - 2019 Feb 15 TI - The Cutting Edge: The Role of mTOR Signaling in Laminopathies. LID - 10.3390/ijms20040847 [doi] LID - 847 AB - 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. FAU - Chiarini, Francesca AU - Chiarini F AD - CNR National Research Council of Italy, Institute of Molecular Genetics, Unit of Bologna, 40136 Bologna, Italy. francesca.chiarini@cnr.it. AD - IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy. francesca.chiarini@cnr.it. FAU - Evangelisti, Camilla AU - Evangelisti C AD - CNR National Research Council of Italy, Institute of Molecular Genetics, Unit of Bologna, 40136 Bologna, Italy. camilla.evangelisti@cnr.it. AD - IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy. camilla.evangelisti@cnr.it. FAU - Cenni, Vittoria AU - Cenni V AUID- ORCID: 0000-0001-8062-1840 AD - CNR National Research Council of Italy, Institute of Molecular Genetics, Unit of Bologna, 40136 Bologna, Italy. vittoria.cenni@cnr.it. AD - IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy. vittoria.cenni@cnr.it. FAU - Fazio, Antonietta AU - Fazio A AD - Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy. antonietta.fazio@studio.unibo.it. FAU - Paganelli, Francesca AU - Paganelli F AD - Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy. francesca.paganell15@studio.unibo.it. FAU - Martelli, Alberto M AU - Martelli AM AUID- ORCID: 0000-0001-5196-7260 AD - Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy. alberto.martelli@unibo.it. FAU - Lattanzi, Giovanna AU - Lattanzi G AUID- ORCID: 0000-0002-7103-8722 AD - CNR National Research Council of Italy, Institute of Molecular Genetics, Unit of Bologna, 40136 Bologna, Italy. giovanna.lattanzi@cnr.it. AD - IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy. giovanna.lattanzi@cnr.it. LA - eng PT - Journal Article PT - Review DEP - 20190215 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Lamins) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Humans MH - Lamins/*metabolism MH - Models, Biological MH - Muscular Dystrophies/*metabolism MH - *Signal Transduction MH - TOR Serine-Threonine Kinases/*metabolism PMC - PMC6412338 OTO - NOTNLM OT - Emery-Dreifuss muscular dystrophy (EDMD) OT - Hutchinson-Gilford progeria syndrome (HGPS) OT - ageing OT - autophagy OT - bone remodeling OT - cellular signaling OT - lamin A/C OT - laminopathies OT - mTOR OT - metabolism COIS- The authors declare no conflict of interest. EDAT- 2019/02/20 06:00 MHDA- 2019/06/01 06:00 PMCR- 2019/02/01 CRDT- 2019/02/21 06:00 PHST- 2019/01/21 00:00 [received] PHST- 2019/02/11 00:00 [revised] PHST- 2019/02/12 00:00 [accepted] PHST- 2019/02/21 06:00 [entrez] PHST- 2019/02/20 06:00 [pubmed] PHST- 2019/06/01 06:00 [medline] PHST- 2019/02/01 00:00 [pmc-release] AID - ijms20040847 [pii] AID - ijms-20-00847 [pii] AID - 10.3390/ijms20040847 [doi] PST - epublish SO - Int J Mol Sci. 2019 Feb 15;20(4):847. doi: 10.3390/ijms20040847.