Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Rep. 2024 Aug 27;43(8):114587. doi: 10.1016/j.celrep.2024.114587. Epub 2024 Aug 7.
Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-dependent gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. Short hairpin RNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of muscle atrophy associated with cancer cachexia and highlight potential therapeutic targets for this disorder.
癌症恶病质是一种普遍且常致命的消耗性疾病，不能仅通过营养干预来完全逆转。肌肉萎缩是该综合征的一个核心组成部分，但癌症导致骨骼肌萎缩的机制尚不清楚。我们对癌症恶病质小鼠模型的骨骼肌进行了单细胞多组学分析，并对恶病质肌肉中的分子变化进行了分析。我们的结果揭示了一种去神经依赖性基因程序的激活，该程序上调了转录因子肌细胞生成素。进一步的研究表明，肌细胞生成素-肌肉生长抑制素途径促进了肌肉萎缩对癌症恶病质的反应。短发夹 RNA 抑制肌细胞生成素或通过过表达其内源性抑制剂卵泡抑素抑制肌肉生长抑制素，可防止小鼠的癌症恶病质诱导的肌肉萎缩。我们的发现揭示了与癌症恶病质相关的肌肉萎缩的分子基础，并强调了该疾病的潜在治疗靶点。
