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Regeneration of neuromuscular synapses after acute and chronic denervation by inhibiting the gerozyme 15-prostaglandin dehydrogenase.
Bakooshli, Mohsen A; Wang, Yu Xin; Monti, Elena; Su, Shiqi; Kraft, Peggy; Nalbandian, Minas; Alexandrova, Ludmila; Wheeler, Joshua R; Vogel, Hannes; Blau, Helen M.
Afiliação
  • Bakooshli MA; Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Wang YX; Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Monti E; Center for Genetic Disorders and Aging, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • Su S; Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Kraft P; Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Nalbandian M; Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Alexandrova L; Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Wheeler JR; Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University, Stanford, CA 94305, USA.
  • Vogel H; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
  • Blau HM; Department of Neuropathology, Stanford University, Stanford, CA 94305, USA.
Sci Transl Med ; 15(717): eadg1485, 2023 10 11.
Article em En | MEDLINE | ID: mdl-37820010
ABSTRACT
To date, there are no approved treatments for the diminished strength and paralysis that result from the loss of peripheral nerve function due to trauma, heritable neuromuscular diseases, or aging. Here, we showed that denervation resulting from transection of the sciatic nerve triggered a marked increase in the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in skeletal muscle in mice, providing evidence that injury drives early expression of this aging-associated enzyme or gerozyme. Treating mice with a small-molecule inhibitor of 15-PGDH promoted regeneration of motor axons and formation of neuromuscular synapses leading to an acceleration in recovery of force after an acute nerve crush injury. In aged mice with chronic denervation of muscles, treatment with the 15-PGDH inhibitor increased motor neuron viability and restored neuromuscular junctions and function. These presynaptic changes synergized with previously reported muscle tissue remodeling to result in a marked increase in the strength of aged muscles. We further found that 15-PGDH aggregates defined the target fibers that are histopathologic hallmarks of human neurogenic myopathies, suggesting that the gerozyme may be involved in their etiology. Our data suggest that inhibition of 15-PGDH may constitute a therapeutic strategy to physiologically boost prostaglandin E2, restore neuromuscular connectivity, and promote recovery of strength after acute or chronic denervation due to injury, disease, or aging.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sinapses / Hidroxiprostaglandina Desidrogenases Limite: Aged / Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sinapses / Hidroxiprostaglandina Desidrogenases Limite: Aged / Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article