Genetic and Pathophysiological Basis of Cardiac and Skeletal Muscle Laminopathies

Figures

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  Figure 1. Lamin structure with mutations linked to laminopathies and crosstalk among signaling pathways. (A) Lamin structure and the location of mutated amino acids. Black: Drosophila (LamC) and red (LMNA) corresponding human numbering. The Drosophila LamC was used to depict the lamin structure with various domains. (B) The crosstalk between autophagy and redox signaling is linked with striated muscle laminopathies. The cytoplasmic aggregation of mutant LamC and other nuclear envelope protein (NEP) impairment triggers cellular and molecular stress, which leads to defective autophagy and impaired redox signaling. Impairment associated with autophagy and redox signaling leads to the inactivation of AMPK and downstream pathways, which produces proteostasis stress and leads to striated muscle laminopathy [57,62].

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  Figure 2. Model for the mechanism of AMPK/TOR/autophagy signaling by cytoplasmic lamin aggregates. Modified from Ref. [62], tissue-specific expression of lamin mutations in the heart and skeletal muscle causes the aggregation of mutant LamC and others (NEP), which causes an upregulation of p62, which ties with the aggregates and directs them for degradation [96]. Abnormal accumulation of p62 leads to autophagy inhibition in the heart and skeletal muscle, which leads to the inactivation of AMPK, which functions to maintain cellular energy homeostasis [114]. The inactivation of AMPK is associated with the hyperactivation of TOR signaling, a pathway associated with cell growth and cell survival [115,116]. In transcriptomics data obtained from muscle biopsy tissue carrying the LMNA-G449V mutation, the above-mentioned genes were upregulated, thereby leading to autophagy inhibition in the cardiac muscle [106]. The upregulation of mTOR activity also causes enhanced S6K activity and leads to an imbalance in energy homeostasis [116,117]. Moreover, AMPK is also known to regulate the expression level of genes associated with SIRT1, a class III histone deacetylase, which is linked with proteostasis…