Background

Given its conserved cardiovascular physiology and genetic amenability, adult zebrafish is an emerging vertebrate model for cardiomyopathy studies (Gut et al., 2017). Since the first evidence of conserved cardiac remodeling processes in this low vertebrate model (Sun et al., 2009), a panel of acquired and inherited cardiomyopathy models has been established in adult zebrafish (Dvornikov et al., 2018). In comparison with rodent models, zebrafish models possess higher throughput that enables forward genetic screens to identify novel genetic modifiers (Ding et al., 2016; Ma et al., 2018) and chemical screens to rapidly assess therapeutic drug candidates for cardiomyopathy. However, phenotyping tools for adult zebrafish models of cardiomyopathy remain a bottleneck, partially due to technical challenges associated with the small size of adult zebrafish.

In human patients with cardiomyopathy and subsequent heart failure, exercise intolerance is an important pathophysiologic hallmark (Del Buono et al., 2019). For example, the stratification of heart failure patients following the New York Heart Association (NYHA) classification guidelines is based heavily on exercise capacity. The 6-min walk test, in particular, is a classic and commonly used quantitative method to determine exercise capacity in clinical settings, which has been used to provide important diagnostic and prognostic information in cardiomyopathy and heart failure patients (Pina et al., 2003; Del Buono et al., 2019). To develop a corresponding phenotyping tool for adult zebrafish models, we recently leveraged a swimming-based assay to evaluate the exercise capacity in a doxorubicin-induced cardiomyopathy (DIC) model (Ma et al., 2020). We found that the critical swimming speed is a useful non-invasive index to validate the successful establishment of the model and evaluate the benefits of therapeutic intervention. Indeed, the swimming assay has also been implemented in studies using zebrafish as models for a variety of purposes including tissue regeneration (Wang et al., 2011; Mokalled et al., 2016), skeletal muscle growth (Palstra et al., 2010), and aging (Gilbert et al., 2014). More recently, a general protocol to measure the critical swimming speed in adult zebrafish has been described in detail (Wakamatsu et al., 2020). Herein, we describe the protocol used in our program for phenotyping an adult zebrafish model of DIC (Ding et al., 2011; Ma et al., 2018). It is anticipated that this protocol can be extended to other adult zebrafish models of cardiovascular diseases (Ding et al., 2020).