Experiments reveal a novel mechanism to regulate myofiber types and its activation by functional food ingredients

摘要

Fast/slow fiber-type proportions are responsible for skeletal muscle properties including: contractility (fast- and slow-twitch), metabolism (glycolytic and oxidative), fatigue resistance (low and high), and sensation (differential tasting-component contents, fat deposition, and texture). Therefore the mechanisms that regulate fiber type and their manipulation are hot targets of research for meat-animal production, human sports, and health sciences. Recently, we found that resident muscle stem satellite cells up-regulate a multi-functional secreted protein, semaphorin 3A (Sema3A) exclusively at the early phase of myogenic differentiation in response to muscle injury; however, its physiological significance is still unknown. The current study encouraged a possible mechanism that impacts the formation of slow-twitch fibers through a novel signaling pathway: the Sema3A ligand binds to its cell-membrane receptor (neuropilin2-plexin A3 complex) which activates myogenin/MEF2D expression to result in slowmyosin synthesis. This was revealed in both siRNA-transfected cultures and satellite cell-specific Sema3A conditional knockout mice. The in vitro knock-down experiments also provided an additional important element that Sema3A-neuropilin 1/plexin Al，A2coupling may enhance slow-fiber formation during myotube formation by activating signals that inhibit fast-myosin heavy chain expression. A subsequent in vivo study showed that an 8-week intake of apple polyphenol (APP; prepared from unripe apples) in the diet, significantly improved muscle endurance based on increased proportions of fatigue-resistant fibers in rat leg muscles. Notably, supplementation of apple polyphenols (500 ng/ml) or the major component, chlorogenic acid (10 ng/ml) up-regulated theexpression of slow myosin, myogenin, and MEF2D in culture, indicating that chlorogenic acid may be a Sema3A-receptor agonist and activate the Sema3A-dependent pathway. By further understanding this scenario where chlorogenic acid drives Sema3A, we willbe able to design new specific ways to target regeneration and fiber-type proportions.