Abstract
Secondary shifts develop in post-translational phosphorylation of sarcomeric proteins in multiple animal models of inherited cardiomyopathy. These signaling alterations together with the primary mutation are predicted to contribute to the overall cardiac phenotype. As a result, identification and integration of post-translational myofilament signaling responses are identified as priorities for gaining insights into sarcomeric cardiomyopathies. However, significant questions remain about the nature and contribution of post-translational phosphorylation to structural remodeling and cardiac dysfunction in animal models and human patients. This perspective essay discusses specific goals for filling critical gaps about post-translational signaling in response to these inherited mutations, especially within sarcomeric proteins. The discussion focuses primarily on pre-clinical analysis of animal models and defines challenges and future directions in this field.
Highlights
More than 3800 gene mutations are linked to inherited cardiomyopathies (ICs) and identification of underlying gene mutations continues to expand
One area which may provide insight into these issues, and deserves further consideration, is dynamic local myofilament signaling and its impact on downstream networks and/or global signaling within cardiac myocytes. This Perspective focuses on the possibility that IC-linked mutations alter local myofilament signaling and contribute to downstream remodeling and disease progression
Our current understanding of dynamic post-translational myofilament signaling is briefly summarized to lay the foundation for future work aimed at investigating relationships between IC-linked mutations and myofilament modulation
Summary
More than 3800 gene mutations are linked to inherited cardiomyopathies (ICs) and identification of underlying gene mutations continues to expand (https://www.ncbi.nlm.nih.gov/clinvar/). In animal models expressing IC-linked mutations, E-C coupling and Ca2+ handling network alterations are often detected in parallel with in vivo evidence of cardiac performance compensation and/or dysfunction, and prior to end-stage heart failure (Ashrafian et al, 2011) These changes in Ca2+ increase the risk for developing arrhythmia and sudden cardiac death (Ashrafian et al, 2011; Yar et al, 2014), and the events responsible for initiating and/or causing remodeling of the Ca2+ signal may be critical for understanding IC-linked disease progression. Poor outcomes are associated with myofilament β-AR uncoupling in other types of human heart failure, and the ability of IC-linked mutations to cause this uncoupling is proposed to be a prognostic indicator in patients with IC-linked mutations (Messer and Marston, 2014)
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