Desmin, the muscle-specific intermediate filament protein, is a major target in dilated cardiomyopathy and heart failure in humans and mice. The hallmarks of desmin-deficient (des^−/−) mice pathology include pronounced myocardial degeneration, extended fibrosis, and osteopontin (OPN) overexpression. We sought to identify the molecular and cellular events regulating adverse cardiac remodelling in des^−/− mice and their potential link to OPN. In situ hybridization, histology, and immunostaining demonstrated that inflammatory cells and not cardiomyocytes were the source of OPN. RNA profile comparison revealed that activation of inflammatory pathways, sustained by innate immunity mechanisms, predominated among all changes occurring in degenerating des^−/− myocardium. The expression of the most highly up-regulated genes (OPN: 226×, galectin-3: 26×, osteoactivin/Gpnmb/DC-HIL: 160× and metalloprotease-12: 98×) was associated with heart infiltrating macrophages. To evaluate the role of OPN, we generated des^−/−OPN^−/− mice and compared their cardiac function and remodelling indices with those of des^−/−. Osteopontin promoted cardiac dysfunction in this model since des^−/−OPN^−/− mice showed 53% improvement of left ventricular function, paralleled to an up to 44% reduction in fibrosis. The diminished fibrotic response in the absence of OPN could be partly mediated by a dramatic reduction in myocardial galectin-3 levels, associated with an impaired galectin-3 secretion by OPN-deficient infiltrating macrophages. Cardiomyocyte death due to desmin deficiency leads to inflammation and subsequent overexpression of a series of remodelling modulators. Among them, OPN seems to be a major regulator of des^−/− adverse myocardial remodelling and it functions at least by potentiating galectin-3 up-regulation and secretion.

The association of desmin with the α-crystallin Β-chain (αΒ-crystallin; encoded by CRYAB), and the fact that mutations in either one of them leads to heart failure in humans and mice, suggests a potential compensatory interplay between the two in cardioprotection. To address this hypothesis, we investigated the consequences of αΒ-crystallin overexpression in the desmin-deficient (Des−/−) mouse model, which possesses a combination of the pathologies found in most cardiomyopathies, with mitochondrial defects as a hallmark. We demonstrated that cardiac-specific αΒ-crystallin overexpression ameliorates all these defects and improves cardiac function to almost wild-type levels. Protection by αΒ-crystallin overexpression is linked to maintenance of proper mitochondrial protein levels, inhibition of abnormal mitochondrial permeability transition pore activation and maintenance of mitochondrial membrane potential (Δψm). Furthermore, we found that both desmin and αΒ-crystallin are localized at sarcoplasmic reticulum (SR)–mitochondria-associated membranes (MAMs), where they interact with VDAC, Mic60 – the core component of mitochondrial contact site and cristae organizing system (MICOS) complex – and ATP synthase, suggesting that these associations could be crucial in mitoprotection at different levels.