Nuclear mechanosignaling in striated muscle diseases

Abstract

Mechanosignaling describes processes by which biomechanical stimuli are transduced into cellular responses. External biophysical forces can be transmitted via structural protein networks that span from the cellular membrane to the cytoskeleton and the nucleus, where they can regulate gene expression through a series of biomechanical and/or biochemical mechanosensitive mechanisms, including chromatin remodeling, translocation of transcriptional regulators, and epigenetic factors. Striated muscle cells, including cardiac and skeletal muscle myocytes, utilize these nuclear mechanosignaling mechanisms to respond to changes in their intracellular and extracellular mechanical environment and mediate gene expression and cell remodeling. In this brief review, we highlight and discuss recent experimental work focused on the pathway of biomechanical stimulus propagation at the nucleus-cytoskeleton interface of striated muscles, and the mechanisms by which these pathways regulate gene regulation, muscle structure, and function. Furthermore, we discuss nuclear protein mutations that affect mechanosignaling function in human and animal models of cardiomyopathy. Furthermore, current open questions and future challenges in investigating striated muscle nuclear mechanosignaling are further discussed.

Nesprin proteins: bridging nuclear envelope dynamics to muscular dysfunction

“…Investigations in rat cardiomyocytes, where desmin or its associated Nesprin-3 were deleted, revealed microtubule-dependent nuclear invagination, leading to DNA damage, disrupted nuclear envelope-chromatin interactions, and transcriptomic alterations. Co-expression of dominant-negative KASH genes mitigated nuclear invagination, suggesting an interaction between microtubules and Nesprin-1 and/or Nesprin-2 in this process [ 35 , 36 ]. Intriguingly, Nesprin-1 Calponin homology (CH) domains Knockout (KO) mice lacking the actin-binding domain of Nesprin-1G exhibited survival without apparent striated muscle defects, suggesting a potentially non-essential role of Nesprin-1G and its homologs in muscle structure and function [ 37 ].…”