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1.
EMBO J ; 38(1)2019 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-30420558

RESUMEN

As a consequence of impaired glucose or fatty acid metabolism, bioenergetic stress in skeletal muscles may trigger myopathy and rhabdomyolysis. Genetic mutations causing loss of function of the LPIN1 gene frequently lead to severe rhabdomyolysis bouts in children, though the metabolic alterations and possible therapeutic interventions remain elusive. Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids. The metabolic lipid imbalance can be traced to an altered fatty acid synthesis and fatty acid oxidation, accompanied by a defect in acyl chain elongation and desaturation. As an underlying cause, we reveal a severe sarcoplasmic reticulum (SR) stress, leading to the activation of the lipogenic SREBP1c/SREBP2 factors, the accumulation of the Fgf21 cytokine, and alterations of SR-mitochondria morphology. Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength of lipin1 mutants. Our data reveal that SR stress and alterations in SR-mitochondria contacts are contributing factors and potential intervention targets of the myopathy associated with lipin1 deficiency.


Asunto(s)
Estrés del Retículo Endoplásmico/genética , Enfermedades Musculares/genética , Fosfatidato Fosfatasa/genética , Retículo Sarcoplasmático/metabolismo , Ácido Tauroquenodesoxicólico/farmacología , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Masculino , Ratones , Ratones Transgénicos , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/metabolismo , Chaperonas Moleculares/farmacología , Chaperonas Moleculares/uso terapéutico , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Enfermedades Musculares/tratamiento farmacológico , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Retículo Sarcoplasmático/efectos de los fármacos , Retículo Sarcoplasmático/patología , Ácido Tauroquenodesoxicólico/uso terapéutico
2.
EMBO J ; 36(6): 736-750, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28242756

RESUMEN

The inactivation of S6 kinases mimics several aspects of caloric restriction, including small body size, increased insulin sensitivity and longevity. However, the impact of S6 kinase activity on cellular senescence remains to be established. Here, we show that the constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) by tuberous sclerosis complex (TSC) mutations induces a premature senescence programme in fibroblasts that relies on S6 kinases. To determine novel molecular targets linking S6 kinase activation to the control of senescence, we set up a chemical genetic screen, leading to the identification of the nuclear epigenetic factor ZRF1 (also known as DNAJC2, MIDA1, Mpp11). S6 kinases phosphorylate ZRF1 on Ser47 in cultured cells and in mammalian tissues in vivo Knock-down of ZRF1 or expression of a phosphorylation mutant is sufficient to blunt the S6 kinase-dependent senescence programme. This is traced by a sharp alteration in p16 levels, the cell cycle inhibitor and a master regulator of senescence. Our findings reveal a mechanism by which nutrient sensing pathways impact on cell senescence through the activation of mTORC1-S6 kinases and the phosphorylation of ZRF1.


Asunto(s)
Envejecimiento , Proteínas del Choque Térmico HSP40/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas Quinasas S6 Ribosómicas/metabolismo , Animales , Células Cultivadas , Proteínas de Unión al ADN , Ratones , Chaperonas Moleculares , Fosforilación , Proteínas de Unión al ARN
3.
Nat Commun ; 11(1): 3200, 2020 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-32581239

RESUMEN

mTOR activation is essential and sufficient to cause polycystic kidneys in Tuberous Sclerosis Complex (TSC) and other genetic disorders. In disease models, a sharp increase of proliferation and cyst formation correlates with a dramatic loss of oriented cell division (OCD). We find that OCD distortion is intrinsically due to S6 kinase 1 (S6K1) activation. The concomitant loss of S6K1 in Tsc1-mutant mice restores OCD but does not decrease hyperproliferation, leading to non-cystic harmonious hyper growth of kidneys. Mass spectrometry-based phosphoproteomics for S6K1 substrates revealed Afadin, a known component of cell-cell junctions required to couple intercellular adhesions and cortical cues to spindle orientation. Afadin is directly phosphorylated by S6K1 and abnormally decorates the apical surface of Tsc1-mutant cells with E-cadherin and α-catenin. Our data reveal that S6K1 hyperactivity alters centrosome positioning in mitotic cells, affecting oriented cell division and promoting kidney cysts in conditions of mTOR hyperactivity.


Asunto(s)
División Celular , Cinesinas/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Miosinas/metabolismo , Enfermedades Renales Poliquísticas/patología , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Animales , Línea Celular , Cinesinas/genética , Ratones , Ratones Mutantes , Mutación , Miosinas/genética , Fosforilación , Enfermedades Renales Poliquísticas/genética , Enfermedades Renales Poliquísticas/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Transducción de Señal , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/metabolismo , Esclerosis Tuberosa/patología , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Proteína 1 del Complejo de la Esclerosis Tuberosa/metabolismo
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