Review: myogenic and muscle toxicity targets of environmental methylmercury exposure

Abstract

A number of environmental toxicants are noted for their activity that leads to declined motor function. However, the role of muscle as a proximal toxicity target organ for environmental agents has received considerably less attention than the toxicity targets in the nervous system. Nonetheless, the effects of conventional neurotoxicants on processes of myogenesis and muscle maintenance are beginning to resolve a concerted role of muscle as a susceptible toxicity target. A large body of evidence from epidemiological, animal, and in vitro studies has established that methylmercury (MeHg) is a potent developmental toxicant, with the nervous system being a preferred target. Despite its well-recognized status as a neurotoxicant, there is accumulating evidence that MeHg also targets muscle and neuromuscular development as well as contributes to the etiology of motor defects with prenatal MeHg exposure. Here, we summarize evidence for targets of MeHg in the morphogenesis and maintenance of skeletal muscle that reveal effects on MeHg distribution, myogenesis, myotube formation, myotendinous junction formation, neuromuscular junction formation, and satellite cell-mediated muscle repair. We briefly recapitulate the molecular and cellular mechanisms of skeletal muscle development and highlight the pragmatic role of alternative model organisms, Drosophila and zebrafish, in delineating the molecular underpinnings of muscle development and MeHg-mediated myotoxicity. Finally, we discuss how toxicity targets in muscle development may inform the developmental origins of health and disease theory to explain the etiology of environmentally induced adult motor deficits and accelerated decline in muscle fitness with aging.

Keywords: Developmental origins of health and disease; Methylmercury; Myogenesis; Myotoxicity; Skeletal muscle.

Figure 1.

A schematic for translating evidence in flies, fish and rodents for early-life environmental exposure to MeHg and impairment of muscle development and maintenance to humans. In the embryo, MeHg targets the developing muscle via enriched MeHg distribution to muscle (1), myogenesis (2), myotube formation (3), myotendinous junction formation (4), and neuromuscular junction formation (5), disrupting embryonic myogenesis early in life. At postnatal stages, MeHg can target adult muscles by interfering with satellite cell-mediated repair of the wear-and-tear damage in muscle (6). The possible modes of action underlying the MeHg-induced myotoxicity are described in each box under each of these MeHg targets in skeletal muscles. Image created with BioRender.com.