Age-dependent Lamin changes induce cardiac dysfunction via dysregulation of cardiac transcriptional programs

Abstract

As we age, structural changes contribute to progressive decline in organ function, which in the heart acts through poorly characterized mechanisms. Utilizing the rapidly aging fruit fly model with its significant homology to the human cardiac proteome, we found that cardiomyocytes exhibit progressive loss of Lamin C (mammalian Lamin A/C homologue) with age. Unlike other tissues and laminopathies, we observe decreasing nuclear size, while nuclear stiffness increases. 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 an adult-specific role for cardiac transcription factors and show that maintenance of Lamin C sustains their expression and prevents age-dependent cardiac decline. Our findings are conserved in aged non-human primates and mice, demonstrating age-dependent nuclear remodeling is a major mechanism contributing to cardiac dysfunction.

Premature aging in genetic diseases: what conclusions can be drawn for physiological aging

“…In such a way, delayed recruitment to DNA damage foci was shown in HGPS for phospho-NBS and MRE11 ( Constantinescu et al, 2010 ), RAD51 and 53BP1 ( Liu et al, 2005 ) which are mainly involved in HR and NHEJ, respectively (see Box 1 ). In analogy, it may be speculated that changes in lamina and lamina associated proteins known to be occurring under specific conditions during physiological aging ( Swift et al, 2013 ; Kristiani et al, 2020 ; Kirkland et al, 2023 ) may contribute to age-induced changes in the recruitment of DNA damage repair (DDR) factors. For instance, recent findings show for lamin B association with 53BP1 and its release upon DDR.…”

Nuclear mechanosignaling in striated muscle diseases

“…In Drosophila larvae with mutated Nesprin, myonuclei deform differently during contractions compared with wild-type flies ( Lorber et al, 2020 ). In an aging context, cardiomyocytes from Drosophila also exhibit decreased Lamin C expression with age, which coincides with decreased nuclear size, increased nuclear stiffness, and altered transcriptional programs ( Kirkland et al, 2023 ). Similarly, aged mice and non-human primates exhibit reduced nuclear size and circularity, with old mice also having reduced Lamin C compared to younger mice ( Kirkland et al, 2023 ).…”

“…In an aging context, cardiomyocytes from Drosophila also exhibit decreased Lamin C expression with age, which coincides with decreased nuclear size, increased nuclear stiffness, and altered transcriptional programs ( Kirkland et al, 2023 ). Similarly, aged mice and non-human primates exhibit reduced nuclear size and circularity, with old mice also having reduced Lamin C compared to younger mice ( Kirkland et al, 2023 ). Moreover, mutant lamins in skeletal muscle associated with laminopathies and muscular dystrophy cause nuclear envelope rupture and DNA damage that correlate with disease severity in both mice and humans ( Earle et al, 2020 ).…”