Collagen VI deficiency: The heart of the matter

Extracellular matrix (ECM) plays essential roles in development, remodeling and mechanical properties of contractile tissues, such as skeletal and cardiac muscles. Deficiency in collagen VI (COLVI), a widely expressed component of ECM, causes skeletal muscle weakness and dysfunction, while cardiac function remains preserved. Interestingly an unexpected protective effect on heart function was suggested in Col6a1 knock-out mice after myocardial infarct, although the underlying pathways are not fully understood to date. We developed another mouse model harboring a nonsense mutation in the Col6a2 gene, leading to complete COLVI deficiency. Mutant animals display a significantly reduced body weight (BW) and recapitulate the skeletal muscle atrophy and dysfunction observed in other models (Solares-Perez et al., in prep). We analyzed cardiac function by echocardiography and ECG throughout the animals' life, which remained unaltered up to 12 months of age. Heart weight (HW) remained stable over time; however a significantly increased HW/BW ratio was detected at 3 months, with an opposite trend at 12 months. At the histological level, no fibrosis nor cardiomyocyte alteration were observed. However, an unexpected decrease in the expression levels of remodeling markers was detected. ECM components and transmembrane complexes were investigated, pointing to the involvement of integrin dimers, known COLVI receptors. Taken together, our data demonstrate an age-dependent adaptation of cardiac muscle in the absence of COLVI, with no major impairment of cardiac function. To further validate this compensatory mechanism, we are currently performing experiments to challenge the cardiac function by constitutively activating the beta-adrenergic pathway, in young and older animals.