Atrophic remodeling of the heart during vitamin d deficiency and insufficiency in a rat model.

Vitamin D deficiency (VDD) is associated with skeletal muscle wasting and impaired cardiac function in humans and animals. However, the molecular events that cause cardiac dysfunction in VDD are poorly understood, and therefore, therapeutic approaches are limited. In the present study, we investigated the effects of VDD on heart function with an emphasis on signaling pathways that regulate anabolism/catabolism in cardiac muscle. A Vitamin D deficient or insufficient rat model was employed. Heart electrical activity was measured by electrocardiography. Gene expression was monitored by qPCR, while protein expression was assessed by western blotting. Catalytic activities of the proteasome, lysosomal cathepsin activity, and apoptotic caspases were measured by fluorimetry. Vitamin D insufficiency and deficiency led to cardiac arrhythmia, a decrease in heart weight, and an increase in apoptosis and interstitial fibrosis.  Ex-vivo cultures of atria revealed an increase in total protein degradation and a decrease in de-novo protein synthesis. The catalytic activities of the major proteolytic systems: ubiquitin-proteasome system, autophagy-lysosome, and calpains were upregulated in the heart of VDD and insufficient rats. In contrast, the mTOR pathway that regulates protein synthesis was suppressed. These catabolic events were exacerbated by a decrease in the expression of myosin heavy chain and troponin genes, as well as decreased expression and activities of metabolic enzymes. These latter changes occurred despite the activation of the energy sensor, AMPK. Our results provide, compelling evidence for cardiac atrophy in Vitamin D deficient rats. Unlike the skeletal muscle, the heart responded to VDD by activating all three proteolytic systems.