Proteasome Stress in Skeletal Muscle Mounts a Long-Range Protective Response that Delays Retinal and Brain Aging [Human]

The proteasome maintains protein quality during aging and disease. Challenges to proteasome function can be compensated by local proteasome stress responses. However, whereas proteasome stress is also sensed systemically is unknown. In Drosophila , we find that proteasome stress in skeletal muscle non-autonomously promotes the degradation of proteasome substrates in distant tissues during aging. Several muscle-secreted factors (myokines) are upregulated by proteasomal stress via C/EBP transcription factors, including the amylase Amyrel, which increases the circulating levels of the disaccharide maltose. Muscle-specific Amyrel overexpression promotes the degradation of proteasome substrates in the aging brain and retina via the transcriptional induction of chaperones and proteases. Conversely, RNAi for maltose transporters worsens proteostasis and reduces the expression of Amyrel-induced genes in the brain. Moreover, maltose preserves protein quality in cell culture and human cortical brain organoids challenged by thermal stress. Thus, proteasome stress in skeletal muscle mounts a systemic adaptive response via amylase/maltose signaling. mRNA profiles of humen cortical brain organoids between control and maltose treatment, and either with heat shock or not, were generated by RNA-seq, in triplicate, using Illumina sequencing platform.

蛋白酶体（proteasome）在衰老与疾病进程中维持蛋白质质量。当蛋白酶体功能受到扰动时，可通过局部蛋白酶体应激应答进行代偿。然而，蛋白酶体应激是否也能被全身性感知，这一问题仍未明确。在果蝇（Drosophila）模型中，我们发现骨骼肌中的蛋白酶体应激可在衰老过程中非自主性地促进远端组织内蛋白酶体底物的降解。多种骨骼肌分泌因子（肌因子，myokines）可在蛋白酶体应激下通过C/EBP转录因子（C/EBP transcription factors）被上调，其中包括淀粉酶Amyrel——其可提升循环系统中二糖麦芽糖的水平。骨骼肌特异性过表达Amyrel，可通过诱导分子伴侣（chaperones）与蛋白酶（proteases）的转录，促进衰老大脑与视网膜内蛋白酶体底物的降解。反之，靶向麦芽糖转运蛋白的RNA干扰（RNAi）会恶化蛋白质稳态（proteostasis），并降低大脑中Amyrel诱导基因的表达水平。此外，麦芽糖可在细胞培养体系以及经受热应激刺激的人类皮层脑类器官（human cortical brain organoids）中维持蛋白质质量。综上，骨骼肌中的蛋白酶体应激可通过淀粉酶/麦芽糖信号通路触发系统性适应性应答。本研究依托Illumina测序平台（Illumina sequencing platform），采用RNA测序（RNA-seq）技术，对对照组、麦芽糖处理组，以及分别经受热应激与否的人类皮层脑类器官进行了三次生物学重复的mRNA表达谱构建。