Zebrafish & Muscle Disease

Why study cardiac & skeletal muscle disease in the zebrafish?

Skeletal muscle development and disease
In humans, muscle makes up to 50% of the bodyweight and generates force for movement, heartbeat, maintenance of body position, regulation of body temperature, breathing etc. Due to its pivotal role, diseases involving muscle are often devastating.

Our research interest group uses the zebrafish as a model system to explore the musculature – its development, maintenance, regeneration, and associated diseases. Zebrafish do not only combine many advantages such as rapid development, effective husbandry or microscope accessibility, but importantly also often closely resemble human conditions, making gained insights directly relevant for human lifestyle and health.

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Figure 1. Switching from (A) bright field to (A’) polarized light highlights the muscle fibers in fish larvae. Berger et al. 2012, BBRC.

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Figure 2. The dystrophin-deficient mutant dmdpc2 has a typical dystrophic muscle, whereas the tropomodulin4 deficiency in tmod4trg induces a myopathy-like pathology. Berger et al. 2012, DMM and Berger et al. 2014, DMM.

Heart development and disease
Congenital heart disease is the most frequent human genetic birth defect, affecting nearly 1% of live births. The pathogenesis of congenital heart disease is highly varied, with spontaneous mutations that affect any of several hundreds of genes accounting for a large proportion of cases. The heart is established in early embryos by fields of progenitor cells that differentiate into contractile cardiomyocytes. These events form distinct atrial and ventricular chambers that are lined on the periphery by epicardial cells and in the lumen by endocardium. Once formed and contracting, the heart maintains perfusion throughout the body and must acquire mass as an organism grows. This cardiac growth is achieved through mechanisms that involve cardiomyocyte hyperplasia and hypertrophy. While the field of molecular cardiovascular biology has matured steadily, gaps remains in our knowledge of how the cardiac chambers acquire their distinct form, and the sequalae by which specific molecular lesions impact these events. Because of their small size, external development, imaging advantages, and growing genetic toolkit, zebrafish have been a key model system for understanding heart development, both as it occurs normally and as affected by inherited mutations.

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Image 1. “Brainbow” image of the surface of a juvenile zebrafish heart, generated by permanent labeling of individual cardiomyocytes in the 3rd day after fertilization. Each color represents a clone of juvenile cardiomyocytes derived from a single embryonic cardiomyocyte. (Image by Vikas Gupta)

Heart disease and regeneration
Heart failure is an epidemic that afflicts tens of millions of people worldwide. The primary cause of systolic heart failure is the massive loss of healthy cardiac muscle, often the result of an acute myocardial infarction (MI). Annually, approximately 900,000 Americans experience an MI event, losing as many as one billion cardiomyocytes. The human heart, and more generally the adult mammalian heart, shows limited natural muscle regeneration in response to MI, and there is no current methodology that successfully stimulates therapeutic heart regeneration. By contrast, zebrafish have arguably the highest natural capacity for cardiac regeneration we know of among laboratory model systems. Studies by multiple laboratories studying zebrafish heart regeneration have revealed that existing cardiomyocytes spared by the trauma, and not a stem cell population, serve as the primary or exclusive source of new cardiac muscle. Additional reports have described key environmental components that facilitate the division of cardiomyocytes after injury. It is emerging that the analogous regenerative machinery present in zebrafish also exists in the mammalian heart, but is not activated to the same extent for significant regeneration. This fundamental concept gives us confidence that studies in zebrafish can reveal methods to gauge and stimulate human heart regeneration.

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Image 2. Regenerating cardiomyocytes in the ventricle of a zebrafish 30 days after amputation. Green fluorescent protein appears in cells that are expressing the gata4 gene. The nuclei of all cells are stained blue. (Image by Kazu Kikuchi)