Molecular mechanisms of exercise as novel therapies for heart failure

The project was successful and resulted in the following measurable achievements: - Five publications (2 published, 1 accepted and 2 submitted) - It served as ground data for 2 master thesis, supervised by the project leader - Several presentations in national and international conferences - Its results and achievements supported a large application for external funding (Unge forskertalenter - Norges forskningsråd), which was granted to the project leader (Jose BN Moreira) in 2018. The application was ranked first among all applicants. - A new translational research line that spans beyond the cardiovascular field, bridging clinical and experimental data to discover potential therapeutic targets also in skeletal muscle disorders. The summary below describes the main scientific findings in the project: The benefits of physical activity in cardiovascular diseases (CVDs) have long been appreciated. However, the molecular mechanisms that trigger and sustain the cardiac benefits of exercise are poorly understood, and it is anticipated that unveiling these mechanisms will identify novel therapeutic targets. In search of these mechanisms we took advantage of unbiased RNA-sequencing (RNA-seq) technology to discover cardiac gene targets whose expression is disrupted in heart failure and rescued by exercise in a rat model. Upon exhaustive validation in a separate rat cohort (qPCR) and human datasets, we shortlisted 16 targets for a cell-based screening, aiming to evaluate whether targeted disruption of these genes with silencing RNA would affect the abundance of a CVD biomarker (BNP, B-type natriuretic peptide) in human cardiomyocytes. Overall, these experiments showed that Proline Dehydrogenase (PRODH) expression is reduced in human failing hearts, rescued by exercise in a rat model of heart failure, and its targeted knockdown increases BNP expression in human cardiomyocytes. On the other hand, overexpression of PRODH increases the abundance of metabolism-related gene transcripts, and PRODH appears to be crucial to sustain normal mitochondrial function and maintenance of ATP levels in human cardiomyocytes in a hypoxic environment, as well as for redox homeostasis in both normoxic and hypoxic conditions. Altogether our findings show that PRODH is a novel molecular target of exercise in failing hearts and highlight its role in cardiomyocyte physiology, thereby proposing PRODH as a potential experimental target for gene therapy in heart failure. In addition to the main heart project, we were able to contribute in other important studies, as follows: - We contributed to a study (published in 2018) investing the effects of physical on muscle skeletal muscle atrophy induced by sciatic nerve injury, as well as potential cellular mechanisms. The findings proved the potential value of exercise in maintaining skeletal muscle proteostasis and slowing down the progression of neurogenic myopathy. - We are also co-authors on a study investigating how intrinsic aerobic capacity modulates post-translational modification of cardiac and skeletal muscle proteins. The study discovered several novel cysteine oxidative post-translational modification, which bring insights on the regulation of cardiac and skeletal muscle oxygen utilization and suggest new therapeutic targets. As a whole, the project provided important contributions for the field of molecular medicine, discovering novel mechanisms underlying the benefits of physical activity and highlighting their potential as therapeutic drug targets. The new mechanisms discovered in this project, as well as its potential future consequences, will hopefully contribute to new medical treatments, in form of improved therapeutics to treat cardiovascular and muscular disorders.