A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyte

Abstract

Rationale: Mechanical forces are transduced to nuclear responses via the linkers of the nucleoskeleton and cytoskeleton (LINC) complex, which couples the cytoskeleton to the nuclear lamina and associated chromatin. While disruption of the LINC complex can cause cardiomyopathy, the relevant interactions that bridge the nucleoskeleton to cytoskeleton are poorly understood in the cardiomyocyte, where cytoskeletal organization is unique. Furthermore, while microtubules and desmin intermediate filaments associate closely with cardiomyocyte nuclei, the importance of these interactions is unknown. Objective: Here, we sought to determine how cytoskeletal interactions with the LINC complex regulate nuclear homeostasis in the cardiomyocyte. Methods and Results: To this end, we acutely disrupted the LINC complex, microtubules, actin, and intermediate filaments and assessed the consequences on nuclear morphology and genome organization in rat ventricular cardiomyocytes via a combination of super-resolution imaging, biophysical, and genomic approaches. We find that a balance of dynamic microtubules and desmin intermediate filaments is required to maintain nuclear shape and the fidelity of the nuclear envelope and lamina. Upon depletion of desmin (or nesprin [nuclear envelope spectrin repeat protein]-3, its binding partner in the LINC complex), polymerizing microtubules collapse the nucleus and drive infolding of the nuclear membrane. This results in DNA damage, a loss of genome organization, and broad transcriptional changes. The collapse in nuclear integrity is concomitant with compromised contractile function and may contribute to the pathophysiological changes observed in desmin-related myopathies. Conclusions: Disrupting the tethering of desmin to the nucleus results in a loss of nuclear homeostasis and rapid alterations to cardiomyocyte function. Our data suggest that a balance of forces imposed by intermediate filaments and microtubules is required to maintain nuclear structure and genome organization in the cardiomyocyte.

Is Desmin Propensity to Aggregate Part of its Protective Function?

“…In addition, since the creation of the Des -/mice in the 1990s, a progeny that is better able to cope with the lack of desmin could have been selected over time. This view is corroborated by a recent study showing heavily impaired nuclear morphology, strikingly reminiscent of progeria's cells, after acute knock-down of desmin via administration of viral vectors carrying a shRNA against desmin in neonatal rat cardiomyocytes and rat hearts [16]. This is not the first report highlighting the importance of the interconnection between nuclear and cytoplasmic IFs in cardiac cells.…”

Microtubule Organization in Striated Muscle Cells

“…(2) Positioning of organelles and intracellular organization [57][58][59][60][61][62][63][64][65]. (3) Mechanotransduction [66].…”

“…How ncMTOC formation at the nuclear envelope contributes to the role of detyrosinated microtubules in cardiomyocytes has yet to be determined. A recent study showed that perinuclear microtubules exert compressive force on cardiomyocytes nuclei that is counteracted by desmin [62]. In the absence of desmin, microtubules form dynamic protrusions and drive nuclear involution that causes DNA damage, loss of association between nuclear lamina and chromatin, and ultimately large transcriptomic changes.…”

Expression profile of SYNE3 and bioinformatic analysis of its prognostic value and functions in tumors

“…In most cases, the expression of SYNE3 was also downregulated in tumor. Recent study showed that knockdown of SYNE3 led to DNA damage, genome organization loss, and transcriptional changes [14], and these events were closely related to tumorigenesis for this mechanism had been reported in SYNE1 [15].…”