• doi: 10.3390/nu14051078
• Published online 2022 Mar 4
• Ayumi Yamamoto,^1,2,* Shinichi Honda,¹ Mineko Ogura,¹ Masanori Kato,¹ Ryuichi Tanigawa,³ Hidemi Fujino,⁴ and Seiji Kawamoto^2,*

Abstract

Sarcopenia is an age-related skeletal muscle atrophy. Exercise is effective in improving sarcopenia via two mechanisms: activation of skeletal muscle satellite cells (SCs) and stimulation of muscle protein synthesis. In contrast, most nutritional approaches for improving sarcopenia focus mainly on muscle protein synthesis, and little is known about SC activation. Here, we investigated the effect of lemon myrtle extract (LM) on SC activation both in vitro and in vivo. Primary SCs or myoblast cell lines were treated with LM or its derived compounds, and incorporation of 5-bromo-2′-deoxyuridine, an indicator of cell cycle progression, was detected by immunocytochemistry. We found that LM significantly activated SCs (p < 0.05), but not myoblasts. We also identified casuarinin, an ellagitannin, as the active compound in LM involved in SC activation. The structure–activity relationship analysis showed that rather than the structure of each functional group of casuarinin, its overall structure is crucial for SC activation. Furthermore, SC activation by LM and casuarinin was associated with upregulation of interleukin-6 mRNA expression, which is essential for SC activation and proliferation. Finally, oral administration of LM or casuarinin to rats showed significant activation of SCs in skeletal muscle (p < 0.05), suggesting that LM and casuarinin may serve as novel nutritional interventions for improving sarcopenia through activating SCs.

Keywords: sarcopenia, skeletal muscle satellite cells, lemon myrtle, Backhousia citriodora, casuarinin, ellagitannin, interleukin-6

1. Introduction

Sarcopenia is an age-related skeletal muscle atrophy and is defined as a progressive and generalized skeletal muscle disorder that involves accelerated loss of muscle mass and function [1]. Progression of sarcopenia is associated with many health risks, such as an increase in falls and fractures, loss of activities of daily living, and poor quality of life [2]. Sarcopenia was estimated to affect approximately 50 million people in 2010 and this number is expected to increase as the number of older adults increases [3]. The primary intervention for improving sarcopenia is exercise, which has been shown to benefit older adults with sarcopenia [1]. Among exercise methods, resistance exercise is recommended for improving sarcopenia, but it should be performed considering the risks of a temporary increase in blood pressure [4] and injury [5]. In contrast, nutritional interventions are simple and safe approaches. Several nutritional approaches for sarcopenia have been reported, including adequate intake of protein [6], vitamin D [7], omega-3 polyunsaturated fatty acids [8], and leucine [9]. However, effective nutritional interventions for sarcopenia have not yet been established [1], partly because the differences in skeletal muscle hypertrophy mechanisms between exercise and nutritional interventions are not fully understood.

Skeletal muscle is composed of multinucleated cells called myofibers. Since myofiber nuclei, or myonuclei, are post-mitotic and cannot divide to produce new myonuclei, new myonuclei are supplied through the proliferation of skeletal muscle satellite cells (SCs) [10]. SCs are localized between the basal membrane and the plasma membrane of myofibers [11]. In adult muscle, SCs normally reside in a quiescent and undifferentiated state. However, when skeletal muscle is stimulated by injury or exercise, SCs are activated, enter the cell cycle, and divide to produce myoblasts. Myoblasts further proliferate, differentiate, fuse into myofibers, and form new myonuclei [12]. In addition, it is known that some myoblasts return to a quiescent state to maintain the SC pool [13]. Verdijk et al. have shown that age-related skeletal muscle atrophy is accompanied by a decline in the number of SCs and that resistance exercise increases both myofiber size and SC numbers in older adults [14]. Furthermore, it has been reported in mice that the number of SCs decreases in disuse muscle atrophy but increases in stand-up exercise training after atrophy [15].

Exercise induces skeletal muscle hypertrophy through both activation of SCs and stimulation of muscle protein synthesis [16]. In contrast, most nutritional approaches induce muscle protein synthesis stimulation, but little is known about their effects on SC activation [17]. In this study, we focused on the differences in skeletal muscle hypertrophy mechanisms induced by exercise and most nutritional interventions and searched for a novel functional food ingredient that activates SCs. We found that the water extract of lemon myrtle (Backhousia citriodora) leaves could activate SCs in vitro; therefore, we further characterized SC activation by the lemon myrtle extract (LM) both in vitro and in vivo. Using in vitro assays, we investigated whether LM specifically activates SCs, and if so, then which compound in LM activates SCs, and by what mechanism LM activates SCs. In addition, we evaluated the effects of oral administration of LM and its active compound to rats on SC activation in skeletal muscle.

Reference:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912364/