Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90007, USA.
Department of Pathology and Laboratory Medicine, UCI Institute for Neurotherapeutics, University of California, Irvine, Irvine, CA 92697, USA.
Cell Rep. 2023 Nov 28;42(11):113436. doi: 10.1016/j.celrep.2023.113436. Epub 2023 Nov 11.
Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy. Muscle-specific TFEB overexpression significantly ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging in direct regulation of CNS health and disease and suggest that skeletal muscle originating factors may act as therapeutic targets against age-associated neurodegenerative disorders.
骨骼肌最近被认为是中枢神经系统（CNS）功能和衰老的调节剂，它分泌具有代谢调节功能的生物活性分子，称为肌因子，这些分子在靶向组织中发挥作用，包括中枢神经系统。在这里，我们报告了一种通过靶向过表达转录因子 E-B（TFEB）来增强骨骼肌溶酶体和线粒体功能的转基因小鼠的产生。我们发现，这种在骨骼肌中产生的抗衰老作用可减少神经炎症和tau 相关病理特征在tau 病小鼠模型中的积累。肌肉特异性 TFEB 的过表达可显著改善蛋白毒性，减少神经炎症，并促进衰老的中枢神经系统的转录重塑，从而保持老年小鼠的认知和记忆能力。我们的研究结果表明，随着年龄的增长，骨骼肌功能的维持可直接调节中枢神经系统的健康和疾病，并提示源自骨骼肌的因子可能是对抗与年龄相关的神经退行性疾病的治疗靶点。
