Intermediate filaments in cardiomyopathy

Abstract

Intermediate filament (IF) proteins are critical regulators in health and disease. The discovery of hundreds of mutations in IF genes and posttranslational modifications has been linked to a plethora of human diseases, including, among others, cardiomyopathies, muscular dystrophies, progeria, blistering diseases of the epidermis, and neurodegenerative diseases. The major IF proteins that have been linked to cardiomyopathies and heart failure are the muscle-specific cytoskeletal IF protein desmin and the nuclear IF protein lamin, as a subgroup of the known desminopathies and laminopathies, respectively. The studies so far, both with healthy and diseased heart, have demonstrated the importance of these IF protein networks in intracellular and intercellular integration of structure and function, mechanotransduction and gene activation, cardiomyocyte differentiation and survival, mitochondrial homeostasis, and regulation of metabolism. The high coordination of all these processes is obviously of great importance for the maintenance of proper, life-lasting, and continuous contraction of this highly organized cardiac striated muscle and consequently a healthy heart. In this review, we will cover most known information on the role of IFs in the above processes and how their deficiency or disruption leads to cardiomyopathy and heart failure.

Drp1 overexpression induces desmin disassembling and drives kinesin-1 activation promoting mitochondrial trafficking in skeletal muscle

“…The presence of insoluble tetramers may be explained by an inefficient desmin assembling leading to the collapse and aggregation of filaments [44]. It is well established that IF are dynamic structures and reversible phosphorylation is a mechanism that plausibly maintains this dynamism affecting its assembling and disassembling [48,49]. In line with this, we found that in Drp/ MC mice desmin was hyperphosphorylated in Ser-31 by a hyperactivated Cdk-1.…”

“…Desmin preserves mitochondria in close proximity to myofibrils and promotes the transfer of the energy. It is able to sense and respond to stress regulating many processes including the gene expression, thus desmin can be considered a mechanosensor and transducer of signals to the nucleus [42,48,50]. Moreover, desmin disruption compromises the cross-talk between mitochondria and other organelles affecting mitochondrial biogenesis and function [48].…”

“…It is able to sense and respond to stress regulating many processes including the gene expression, thus desmin can be considered a mechanosensor and transducer of signals to the nucleus [42,48,50]. Moreover, desmin disruption compromises the cross-talk between mitochondria and other organelles affecting mitochondrial biogenesis and function [48]. At P7 we observed induction of fission and desmin phospho-Ser-31 positive aggregates, while the mitochondrial repositioning, with subsarcolemmal clumping, and the impaired mitochondrial biogenesis occurred at P25 in Drp/MC mice.…”

Amelioration of desmin network defects by αB-crystallin overexpression confers cardioprotection in a mouse model of dilated cardiomyopathy caused by LMNA gene mutation

“…Mutations on the LMNA gene are associated with more than 10 clinical pathologies, known as laminopathies, with DCM and skeletal myopathies being among the most common ones which can occur isolated or in association with disorders affecting other tissues [5,12,14]. On the other hand, dysfunctional desmin network due to desmin gene mutations or posttranslational modifications (PTMs) causes a wide range of clinical and pathological manifestations, mainly hallmarked by abnormal desmin positive sarcoplasmic aggregates, which are collectively called desminopathies [2,[15][16][17][18][19]. Importantly, mutations in the small heat shock protein Β-Crystallin (ΒCry) also cause desmin aggregate-related DCM and HF [1,2,[20][21][22].…”

Contribution of DNA methylation in chronic stress‐induced cardiac remodeling and arrhythmias in mice

“…Thus, it is possible that the changes in DNA methylation that we observed are due to a change in cell‐type composition in the CRS hearts rather than an alteration in DNA methylation in cardiomyocytes (57). However, in the case of desmin and Adra1b , the change in methylation is likely specific to cardiomyocytes and not caused by recruitment of noncardiomyocyte cells such as fibroblasts and endothelial cells, because desmin is a muscle‐specific gene (58) and Adra1b is predominantly expressed in cardiomyocytes (59). Whether altered methylation of desmin or Adra1b , and the consequent change in their expression, is causal of, rather than correlational to, the LV chamber dilatation that we observed in CRS mice is unclear.…”