Impairment of ultrastructure and cytoskeleton during progression of cardiac hypertrophy to heart failure

Abstract

Studies at the morphological and molecular level have found that transgenic (Tg) mice that overexpress myotrophin in the heart develop hypertrophy at the early age of 4 weeks; this condition worsens to heart failure (HF) at approximately 36 weeks. However, how the sustained effects of alteration in cytoarchitecture of the contractile machinery lead to malfunction of the normal heart remains unclear. Our data have shown that at 4 weeks, the cytoarchitecture observed in left ventricular (LV) tissue samples of Tg mice is similar to that of wild-type (WT) mice. However, as the disease progresses, cardiomyocytes show deterioration in some mitochondrial as well as myofibril features, evidenced by swelling of mitochondria, misalignment of myofibril structure, and blurring as well as breakage of Z-lines. At 36 weeks of age, Tg mice (the group in transition from hypertrophy to HF) show significant degenerative changes in cardiomyocytes, including swelling of mitochondria, disruption of the nuclear membrane, and absence of myofibril structure. Besides these, formation of myelin bodies was also observed, a feature typically found in human hearts with HF. Changes in Z-line architecture were further confirmed by alteration in the gene expression profile of desmin and tubulin, the two main cytoskeletal proteins. We thus conclude that Tg mice overexpressing myotrophin show no visible changes in the initiation phase (4 weeks); however, as the disease progresses, alterations in the cytoskeleton are found during the transition phase from hypertrophy to HF (36 weeks onward). Our data suggest that treatment for prevention/reversal of hypertrophy should start at the early stage of hypertrophy to prevent its transition to HF.

RNA-sequencing analysis reveals new alterations in cardiomyocyte cytoskeletal genes in patients with heart failure

“…Among the differentially expressed genes, some were previously associated with HF, such as ACTA1, VCL, NEB, and MYH6. 21,22 Furthermore, the RNA-Seq results were consistent with data from previous studies. It is well described that the upregulation of collagen genes has been associated with the fibrosis process 27 and the increased expression of membrane-associated proteins, such as VLC, 9 has an adaptive response to cellular integrity loss.…”

Disruption of MEF2C signaling and loss of sarcomeric and mitochondrial integrity in cancer-induced skeletal muscle wasting

“…These changes included electron-lucent areas which corresponded to a loss of cristae in these mitochondria; suggesting defective oxidative phosphorylation to generate ATP. In addition, swollen mitochondria, which are reported to be associated with cellular ATP depletion, were present [29]. Vesicle-like structures, likely to be autophagic bodies were also observed in some mitochondria which suggested eventual mitochondrial loss via autophagy in cachectic muscle [31].…”

Systolic dysfunction in cardiac-specific ligand-inducible MerCreMer transgenic mice

“…Previous studies (10,11) have shown that beta tubulin increases in animal models of heart failure, and it is thought that the accumulation of cytoskeletal proteins like tubulin can reduce contractile function of the heart through interfering with contractile proteins or depleting energy reserves by utilizing ATP for synthesis. Increases in cytoskeletal proteins such as tubulin, however, may be a compensatory mechanism of the cardiomyocyte to adapt to the cellular disruption that occurs in response to increases in diastolic filling pressure and wall stress associated with Cre activation and transient systolic dysfunction in this model (16).…”