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<p>Skeletal muscle wasting is a defining feature of cancer cachexia, a multifactorial syndrome that drastically compromises patient quality of life and treatment outcomes. Mitochondrial dysfunction is a major contributor to skeletal muscle wasting in cancer cachexia, yet the upstream molecular drivers remain elusive. Here we show that cancer impairs the activity of cAMP-dependent protein kinase A (PKA) and of its transcriptional effector CREB1 in skeletal muscle, ultimately contributing to the downregulation of a core transcriptional network that supports mitochondrial integrity and function. The restoration of cAMP–PKA–CREB1 signalling through pharmacological inhibition of the cAMP-hydrolysing phosphodiesterase 4 (PDE4) rescues the expression of mitochondrial-related genes, improves mitochondrial function and mitigates skeletal muscle wasting in male mice. Altogether, our data identify tumour-induced suppression of the cAMP–PKA–CREB1 axis as a central mechanism contributing to mitochondrial dysfunction in skeletal muscle during cancer cachexia. Furthermore, these findings highlight PDE4, particularly the PDE4D isoform, as a potential therapeutic target to preserve muscle mitochondrial function and counteract muscle wasting in cancer cachexia.</p>

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Impaired cAMP–PKA–CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月12日

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  • Elia Angelino,
  • Lorenza Bodo,
  • Roberta Sartori,
  • Valeria Malacarne,
  • Beatrice D’Anna,
  • Nicolò Formaggio,
  • Suvham Barua,
  • Tommaso Raiteri,
  • Andrea Lauria,
  • Simone Reano,
  • Alessandra Murabito,
  • Monica Nicolau,
  • Fabiana Ferrero,
  • Camilla Pezzini,
  • Giulia Rossino,
  • Francesco Favero,
  • Michele Valmasoni,
  • Nicoletta Filigheddu,
  • Alessio Menga,
  • Davide Corà,
  • Emilio Hirsch,
  • Salvatore Oliviero,
  • Vittorio Sartorelli,
  • Valentina Proserpio,
  • Alessandra Ghigo,
  • Marco Sandri,
  • Paolo E. Porporato,
  • Daniela Talarico,
  • Giuseppina Caretti,
  • Andrea Graziani

摘要

Skeletal muscle wasting is a defining feature of cancer cachexia, a multifactorial syndrome that drastically compromises patient quality of life and treatment outcomes. Mitochondrial dysfunction is a major contributor to skeletal muscle wasting in cancer cachexia, yet the upstream molecular drivers remain elusive. Here we show that cancer impairs the activity of cAMP-dependent protein kinase A (PKA) and of its transcriptional effector CREB1 in skeletal muscle, ultimately contributing to the downregulation of a core transcriptional network that supports mitochondrial integrity and function. The restoration of cAMP–PKA–CREB1 signalling through pharmacological inhibition of the cAMP-hydrolysing phosphodiesterase 4 (PDE4) rescues the expression of mitochondrial-related genes, improves mitochondrial function and mitigates skeletal muscle wasting in male mice. Altogether, our data identify tumour-induced suppression of the cAMP–PKA–CREB1 axis as a central mechanism contributing to mitochondrial dysfunction in skeletal muscle during cancer cachexia. Furthermore, these findings highlight PDE4, particularly the PDE4D isoform, as a potential therapeutic target to preserve muscle mitochondrial function and counteract muscle wasting in cancer cachexia.