Department of Bioengineering, University California San Diego; La Jolla, CA, USA 92093.
Sanford Consortium for Regenerative Medicine; La Jolla, CA, USA 92037.
Nat Aging. 2023 Jan;3(1):17-33. doi: 10.1038/s43587-022-00323-8. Epub 2022 Dec 22.
As we age, structural changes contribute to progressive decline in organ function, which in the heart act through poorly characterized mechanisms. Taking advantage of the short lifespan and conserved cardiac proteome of the fruit fly, we found that cardiomyocytes exhibit progressive loss of Lamin C (mammalian Lamin A/C homologue) with age, coincident with decreasing nuclear size and increasing nuclear stiffness. Premature genetic reduction of Lamin C phenocopies aging's effects on the nucleus, and subsequently decreases heart contractility and sarcomere organization. Surprisingly, Lamin C reduction downregulates myogenic transcription factors and cytoskeletal regulators, possibly via reduced chromatin accessibility. Subsequently, we find a role for cardiac transcription factors in regulating adult heart contractility and show that maintenance of Lamin C, and cardiac transcription factor expression, prevents age-dependent cardiac decline. Our findings are conserved in aged non-human primates and mice, demonstrating that age-dependent nuclear remodeling is a major mechanism contributing to cardiac dysfunction.
随着年龄的增长，结构变化导致器官功能逐渐下降，这在心脏中通过尚未充分阐明的机制起作用。我们利用果蝇寿命短和心脏蛋白组保守的特点，发现心肌细胞随年龄增长逐渐丧失 Lamin C（哺乳动物 Lamin A/C 同源物），同时核体积减小，核硬度增加。过早的基因减少 Lamin C 可模拟衰老对核的影响，随后降低心脏收缩力和肌节组织。令人惊讶的是，Lamin C 的减少会下调肌生成转录因子和细胞骨架调节剂，可能是通过降低染色质可及性。随后，我们发现心脏转录因子在调节成人心肌收缩力方面的作用，并表明维持 Lamin C 和心脏转录因子的表达可以防止与年龄相关的心脏衰退。我们的研究结果在老年非人类灵长类动物和小鼠中得到了保守，表明与年龄相关的核重塑是导致心脏功能障碍的主要机制之一。
