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1.
Stem Cells ; 35(7): 1733-1746, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28436144

RESUMO

Muscle regeneration depends on satellite cells (SCs), quiescent precursors that, in consequence of injury or in pathological states such as muscular dystrophies, activate, proliferate, and differentiate to repair the damaged tissue. A subset of SCs undergoes self-renewal, thus preserving the SC pool and its regenerative potential. Unacylated ghrelin (UnAG) is a circulating hormone that protects muscle from atrophy, promotes myoblast differentiation, and enhances ischemia-induced muscle regeneration. Here we show that UnAG increases SC activity and stimulates Par polarity complex/p38-mediated asymmetric division, fostering both SC self-renewal and myoblast differentiation. Because of those activities on different steps of muscle regeneration, we hypothesized a beneficial effect of UnAG in mdx dystrophic mice, in which the absence of dystrophin leads to chronic muscle degeneration, defective muscle regeneration, fibrosis, and, at later stages of the pathology, SC pool exhaustion. Upregulation of UnAG levels in mdx mice reduces muscle degeneration, improves muscle function, and increases dystrophin-null SC self-renewal, maintaining the SC pool. Our results suggest that UnAG has significant therapeutic potential for preserving the muscles in dystrophies. Stem Cells 2017;35:1733-1746.


Assuntos
Distrofina/genética , Grelina/genética , Músculo Esquelético/metabolismo , Distrofia Muscular Animal/metabolismo , Regeneração/genética , Células Satélites de Músculo Esquelético/metabolismo , Acilação , Animais , Contagem de Células , Diferenciação Celular , Distrofina/metabolismo , Fibrose , Regulação da Expressão Gênica , Grelina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Músculo Esquelético/patologia , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/patologia , Fenótipo , Células Satélites de Músculo Esquelético/patologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
EMBO Mol Med ; 16(6): 1379-1403, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38684863

RESUMO

Polycystic kidney disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4-ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.


Assuntos
Aspartato-Amônia Ligase , Modelos Animais de Doenças , Doenças Renais Policísticas , Animais , Humanos , Camundongos , Aspartato-Amônia Ligase/metabolismo , Aspartato-Amônia Ligase/genética , Aspartato-Amônia Ligase/antagonistas & inibidores , Progressão da Doença , Rim/patologia , Rim/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Doenças Renais Policísticas/metabolismo , Doenças Renais Policísticas/tratamento farmacológico , Doenças Renais Policísticas/patologia , Doenças Renais Policísticas/genética
3.
Cancers (Basel) ; 12(11)2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33233657

RESUMO

NRF2 is a transcription factor that coordinates the antioxidant response in many different tissues, ensuring cytoprotection from endogenous and exogenous stress stimuli. In the kidney, its function is essential in appropriate cellular response to oxidative stress, however its aberrant activation supports progression, metastasis, and resistance to therapies in renal cell carcinoma, similarly to what happens in other nonrenal cancers. While at the moment direct inhibitors of NRF2 are not available, understanding the molecular mechanisms that regulate its hyperactivation in specific tumor types is crucial as it may open new therapeutic perspectives. Here, we focus our attention on renal cell carcinoma, describing how NRF2 hyperactivation can contribute to tumor progression and chemoresistance. Furthermore, we highlight the mechanism whereby the many pathways that are generally altered in these tumors converge to dysregulation of the KEAP1-NRF2 axis.

4.
Bio Protoc ; 8(2): e2696, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-34179245

RESUMO

Satellite cell (SC) transplantation represents a powerful strategy to investigate SC biology during muscle regeneration. We described here a protocol for SC isolation from green fluorescent protein (GFP)-expressing mice and their transplantation into murine muscles. This procedure was originally used to assess the effects of the hormone unacylated ghrelin on muscle regeneration, in particular evaluating how the increase of unacylated ghrelin in the recipient muscle affected the engraftment of donor SCs ( Reano et al., 2017 ).

5.
Endocrine ; 62(1): 129-135, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29846901

RESUMO

PURPOSE: Muscle regeneration depends on satellite cells (SCs), quiescent precursors that, in consequence of injury or pathological states such as muscular dystrophies, activate, proliferate, and differentiate to repair the damaged tissue. A subset of SCs undergoes self-renewal, thus preserving the SC pool and its regenerative potential. The peptides produced by the ghrelin gene, i.e., acylated ghrelin (AG), unacylated ghrelin (UnAG), and obestatin (Ob), affect skeletal muscle biology in several ways, not always with overlapping effects. In particular, UnAG and Ob promote SC self-renewal and myoblast differentiation, thus fostering muscle regeneration. METHODS: To delineate the endogenous contribution of preproghrelin in muscle regeneration, we evaluated the repair process in Ghrl-/- mice upon CTX-induced injury. RESULTS: Although muscles from Ghrl-/- mice do not visibly differ from WT muscles in term of weight, structure, and SCs content, muscle regeneration after CTX-induced injury is impaired in Ghrl-/- mice, indicating that ghrelin-derived peptides actively participate in muscle repair. Remarkably, the lack of ghrelin gene impacts SC self-renewal during regeneration. CONCLUSIONS: Although we cannot discern the specific Ghrl-derived peptide responsible for such activities, these data indicate that Ghrl contributes to a proper muscle regeneration.


Assuntos
Grelina/metabolismo , Músculo Esquelético/metabolismo , Regeneração/fisiologia , Células Satélites de Músculo Esquelético/metabolismo , Animais , Grelina/genética , Masculino , Camundongos , Camundongos Knockout
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