"Muscling" Throughout Life: Integrating Studies of Muscle Development, Homeostasis, and Disease in Zebrafish.

The proper development and function of skeletal muscle is vital for health throughout the lifespan. Skeletal muscle function enables posture, breathing, and locomotion; and also impacts systemic processes-such as metabolism, thermoregulation, and immunity. Diseases of skeletal muscle (myopathies, muscular dystrophies) and even some neurological, age-related, and metabolic diseases compromise muscle function and negatively affect health span and quality of life. There have been numerous, recent examples of studies on skeletal muscle development with exciting, therapeutic implications for muscle diseases. The zebrafish (Danio rerio) is a vertebrate model organism well accepted for developmental biology and biomedical research and thus an ideal system in which to elucidate the translational implications of mechanisms regulating skeletal muscle development and homeostasis. Muscle fiber types (slow- vs fast-twitch) are spatially segregated in zebrafish allowing for the opportunity to identify distinct mechanisms regulating fiber type specification during development as well as observe fiber type-specific effects in zebrafish models of muscle diseases. Accessible genetics coupled with transparent zebrafish embryos has enabled in vivo cell biology experiments allowing for the visualization and understanding of never-before-seen cellular processes occurring in muscle development, regeneration, and disease. In addition, high-throughput drug screening provides a platform for efficient drug discovery. The purpose of this chapter is to review the studies in zebrafish that significantly contributed to our understanding of cellular and molecular mechanisms regulating skeletal muscle development, homeostasis, or disease in vertebrates, with a particular emphasis on the basic developmental biology studies with promising therapeutic implications.

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish.

Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in cancer treatment and in a number of curative and palliative regimens. Despite its beneficial effects on cancer, paclitaxel also damages healthy tissues, most prominently the peripheral sensory nervous system. The mechanisms leading to paclitaxel-induced peripheral neuropathy remain elusive, and therapies that prevent or alleviate this condition are not available. We established a zebrafish in vivo model to study the underlying mechanisms and to identify pharmacological agents that may be developed into therapeutics. Both adult and larval zebrafish displayed signs of paclitaxel neurotoxicity, including sensory axon degeneration and the loss of touch response in the distal caudal fin. Intriguingly, studies in zebrafish larvae showed that paclitaxel rapidly promotes epithelial damage and decreased mechanical stress resistance of the skin before induction of axon degeneration. Moreover, injured paclitaxel-treated zebrafish skin and scratch-wounded human keratinocytes (HEK001) display reduced healing capacity. Epithelial damage correlated with rapid accumulation of fluorescein-conjugated paclitaxel in epidermal basal keratinocytes, but not axons, and up-regulation of matrix-metalloproteinase 13 (MMP-13, collagenase 3) in the skin. Pharmacological inhibition of MMP-13, in contrast, largely rescued paclitaxel-induced epithelial damage and neurotoxicity, whereas MMP-13 overexpression in zebrafish embryos rendered the skin vulnerable to injury under mechanical stress conditions. Thus, our studies provide evidence that the epidermis plays a critical role in this condition, and we provide a previously unidentified candidate for therapeutic interventions.