Soybean isoflavones potentially prevent sarcopenia: a systematic review

Abstract

Background

Soybean is an important food resource that has been used for centuries in Korean cuisine. Soybean is considered a good source of protein and a nutritional powerhouse. Isoflavone, one of the components of soybean, has been investigated for its nutritional role and physiological effects. As soybean can supply sufficient proteins for muscle and soybean isoflavone might have a direct effect on muscle, soybean could be a potential nutritional treatment for muscle atrophy. However, the effect of isoflavone on muscle atrophy is controversial.

Methods

Four in vitro studies and four in vivo studies were selected from the literature to determine the potential capacity of isoflavones as preventers of sarcopenia.

Results

In vitro and in vivo studies, there have been studies that isoflavone extracted from soybean is effective in preventing muscle atrophy. Research on soybean isoflavone and muscle loss included in this study showed that soybean isoflavone may prevent myotube atrophy by blocking the expression of MuRF1 or by regulating androgen receptors. Isoflavone has been shown to increase the diameter of myoblasts and increase muscle mass.

Conclusion

The present study showed the potential of soy isoflavones as a preventer of sarcopenia by preventing muscle loss.

Introduction

Rich flavors, vivid colors, and distinctive culinary traditions are hallmarks of Korean food. One of the Korean foods is soybean, which has played a pivotal role in shaping Korean cuisine for centuries reflecting both nutritional and cultural value [1]. They have been developed in a variety of fermented items, including sauces and pastes [2].

In Korean cuisine, soybean serves to enhance flavor. One of the most well-known examples is a soy sauce called Kanjang. Kanjang is a crucial ingredient in Korean cooking because it gives dishes a savory depth of flavor and a distinct umami flavor. Doenjang, a different fermented soybean paste, is additionally used as a foundation for soups and stews adding a potent umami flavor that enhances the flavor profile of these foods [1].

Korea is also considered the origin of soybean. This is because wild soybeans, medium soybeans, and cultivated soybeans grow in one place in the Korean Peninsula and Manchuria, and carbonized soybeans, the remains of soybeans, have been consistently excavated from the Korean Peninsula from the Neolithic Age to the Bronze Age [3]. This indicates that not only were soybeans being grown, but they had also spread to the point where Koreans were eating food made with them [4]. As a result, Korea could create meals made from soybeans like tofu, Doenjang, and Kanjang since ancient times [5].

Soybean is considered a nutritional powerhouse as it contains dietary fiber, vitamins, and minerals, including iron, calcium, and B vitamins [6]. The composition of general soybean seeds is carbohydrates (31.7–31.85%), proteins (32–43.6%), fat (15.5–24.7%), water (5.6–11.5%), crude ash (4.5–6.4%), neutral detergent fiber (10–14.9%), and acid detergent fiber (9–11.1%) [7]. Isoflavone, one of the components of soybean, has been investigated for its nutritional role and physiological effects [8]. Isoflavones have a limited natural distribution. They are only found in physiologically meaningful concentrations in soybeans and foods derived from this legume among regularly consumed foods [9]. Isoflavones including the 3 aglycones genistein (4',5,7-trihydroxyisoflavone), daidzein (4',7-dihydroxyisoflavone), and glycitein (7,4'-dihydroxy-6-methoxyisoflavone) are found in about 25 mg per serving of traditional soy foods (Fig. 1) [10, 11].

Fig. 1

Structure of isoflavone. A Daidzin; B Glycitin; C Genistin. Glc = Glycoside

Isoflavones have a phenolic ring with agonistic and antagonistic effects on the estrogen receptor (ER) α and ERβ [12, 13]. There have been concerns raised about the potential negative consequences of soy consumption on men, such as feminization and infertility [14, 15]. Isoflavones have nongenomic effects that regulate a variety of intracellular signaling cascades in addition to estrogen receptor binding [16]. Isoflavones also may alter the activity of enzymes involved in hormone production and metabolism [17]. Therefore, isoflavone has been considered as having the potential to be a natural alternative to conventional hormone therapy for postmenopausal women [18].

There are 12 soybean isoflavone isomers belonging to three aglycones of different conjugated forms (β-glucoside, acetylglucoside, and malonylglucoside): genistein, daidzein, and glycitein [19]. Abundantly present in soy products, they are well known for their estrogenic action. Isoflavone might have a direct influence on muscle by structurally and weakly binding affinity for estrogen receptor (ER), which is 100–1000 times lower than estradiol [20, 21]. In both smooth and skeletal muscle cells, ERs have been measured [22]. It has been demonstrated that estrogen can decrease skeletal muscle energy loss and improve cell membranes [23]. Therefore, isoflavones can bind to and transactivate estrogen receptors. They have molecular structures comparable to estrogen [24]. The study of Ji et al. [25] has shown that genistein can limit L8 myoblast proliferation, fusion, and myotube protein synthesis. In contrast, the study of Pan et al. [26] has demonstrated that genistein, daidzein, and glycitein can inhibit smooth cell proliferation.

Sarcopenia is a muscle atrophy caused by the loss of muscular mass, strength, and function that occurs as people age [27]. Muscle atrophy is caused by a decrease in protein synthesis and an increase in proteolysis [28]. Because muscle is an endocrine organ, muscle atrophy of sarcopenia is directly involved in metabolic disease. Decreased secretion of sex hormones such as estrogen and testosterone is related to skeletal muscle loss [29, 30]. Intake of soybean isoflavone might be a potential nutritional treatment for muscle atrophy as soybean isoflavone has a capacity toward estrogen receptors (ERs). As soybean can supply sufficient proteins for muscle and soybean isoflavone might have a direct effect on muscle, soybean could be a potential nutritional treatment for muscle atrophy. However, the effect of isoflavone on muscle atrophy is controversial.

Soybeans and Soybean isoflavones have been studied for their potential role in preventing the age-related muscle loss associated with sarcopenia. Overall understanding of the relationship between soybean isoflavones and muscle loss could develop the potential usability of Korean soybean. This study systematically reviews the previous in vitro and in vivo studies in determining the effect of soybean isoflavone on muscle. Four in vitro and four in vivo studies were selected for the present systematic review.

Materials and methods

The literature search was conducted in PubMed/MEDLINE database to identify relevant studies. The search was carried out between January 1st, 2005 and September 30th, 2021. This study used the following search terms: ("soybean s"[All Fields] OR "soybeans"[MeSH Terms] OR "soybeans"[All Fields] OR "soybean"[All Fields]) AND ("muscle, skeletal"[MeSH Terms] OR ("muscle"[All Fields] AND "skeletal"[All Fields]) OR "skeletal muscle"[All Fields] OR ("skeletal"[All Fields] AND "muscle"[All Fields])). MeSH (Medical Subject Headings) serves as the National Library of Medicine's controlled vocabulary thesaurus, used for indexing of articles for PubMed. The terms in [] are commands to search the relevant area (or term). [MeSH Terms] is a command to perform a search in the MeSH area, and [All Fields] is a term to search in all saved areas of the paper without limitation. A total of 463 articles were identified from the database (Fig. 2), and 352 articles were removed by title and abstract screening. After the full-text screening, 85 articles that have no relation to soybean and skeletal muscle were also removed. 18 records were excluded additionally because they did not describe detailed application methods for soybean or isoflavones and failed to provide sufficient data for muscle atrophy. Finally, 8 unique articles were included in the present study (Fig. 3).

Fig. 2

The results obtained from the PubMed/Medline search

Fig. 3

Flowchart of literature selection process

Additionally, we sorted out articles that included content about the association of soybean isoflavone with muscle change. Articles were divided into two groups: a group of in vitro studies and a group of in vivo studies.

Results and discussion

In vitro studies

Four in vitro studies about the association of soybean isoflavone with muscle change were included (Table 1) [28, 31,32,33]. According to the study of Jones et al. [31], soy isoflavones including genistein, daidzein, glycitein are associated with endogenous estrogens. In that study, a proliferation of Rat L6 myogenic cells was inhibited by a supplement with genistein. Additionally, genistein, daidzein, and glycitein slightly stimulated protein synthesis. Genistein, which has the capacity as an inhibitor of receptor tyrosine kinase, could affect cell growth [34]. Genistein might be involved in the cell cycle by inhibiting tyrosine kinases, which could affect the mitosis-promoting factor complex. This could obstruct the cell cycle, thus inhibiting proliferation [34]. Compared to genistein, other isoflavones such as daidzein and glycitein might not have as strong affinity for ER binding sites. For binding to the ER, genistein competes with E2, preferring estrogen receptor α (ERα) over estrogen receptor β (ERβ). In addition, it has been observed that glycitein has little influence on muscle cell proliferation [24]. As ERs in skeletal muscle cells have not been precisely characterized, the present study could contribute to the understanding of whether the response of one ER is more prevalent than that of another receptor.

Table 1 In vitro studies about the influence of soybean isoflavone on muscle

The study of Hirasaka et al. [28] showed that myotube atrophy induced by TNF-α could be blocked by genistein and daidzein. These isoflavones could inhibit muscle RING-finger protein 1 (MuRF1) promoter activity which is stimulated by TNF-α inflammatory cytokines. They also reported that genistein and daidzein could induce the phosphorylation of AMP-activated protein kinase (AMPK) in C2C12 myotubes. AMPK has been demonstrated to be able to indirectly activate SIRT1 by increasing intracellular NAD + levels [28]. This suggests that inhibitory effects of isoflavones are mediated not just by estrogen receptor-mediated activation of sirtuin 1 (SIRT1), but also by additional routes that activate AMPK phosphorylation in C2C12 myotubes.

In mammals, skeletal muscle is made up of four types of fibers, including oxidative slow-twitch type I, oxidative fast-twitch IIA, glycolytic fast-twitch IIB, and IIX/D [35]. In these types of fibers, the isoform of myosin heavy chain (MyHC) is expressed. Saneyasu et al. [32] have shown that soy isoflavones can increase Myh7, which is a slow type of myosin heavy chain in C2C12 cells. According to their study, roasted soybean-germ powder (containing 40% protein), soybean meal (containing 45% protein), and soybean-term protein (containing 65% protein) upregulated mRNA expression levels of MyH7 in C2C12 myotubes [32]. In contrast, mRNA levels of Myh4, a fast-type myosin heavy chain, were decreased by isoflavone. Their study also showed that soy isoflavones extracted from soybean-germ could significantly increase MyHC1, which is encoded by Myh7 in the extensor digitorum longus. These results show that isoflavone is closely related to muscle fiber.

Zheng et al. [33] have shown that soy extract (5.3 mg/g genistein, 10.4 mg/g daidzein, 3.2 mg/g glycitein) can increase the diameters of C2C12 myotubes. According to their study, isoflavone aglycones, especially genistein, can induce anabolic effects on C2C12 myotubes by binding to ER and increasing insulin-like growth factor 1 (IGF-1). Many studies have demonstrated that inactivation of IGF-1 can inhibit muscle growth by reducing muscle fiber number and size [36, 37]. IGF-1 is also known to be able to increase muscle mass by decreasing MuRF1. MuRF1 is a muscle-specific ubiquitin ligase that is thought to play a role in muscle atrophy [38]. Therefore, isoflavones of soy extracts can affect muscle fiber via IGF-1, not directly by regulating MuRF1 gene expression.

In vivo studies

There are four in vivo studies about the association of soybean isoflavone with muscle change (Table 2) [27, 39,40,41]. The study of Kataoka et al. [39] concluded that the soy germ protein concentrate diet (SGPC group) could enhance muscle hypertrophy than casein diet (C group) for Wistar rats. Weights of the gastrocnemius, plantaris, tibialis anterior, hindlimb muscle, and total hindlimb muscles were significantly higher in the SGPC group than in the C group. The study of Park et al. [27] showed that silk peptide was quickly absorbed, which might have protected against the reduction of grip strength in middle-aged female rats. However, their study was limited to middle-aged Sprague Dawley female obesity rats.

Table 2 In vivo studies about the influence of soybean isoflavone on muscle

Qiang et al. [41] conducted an experiment with spinal and bulbar muscular atrophy (SBMA) transgenic mice and provided a soy-free diet or identical diet supplemented with genistein. Their results showed that genistein treatment promoted mutant androgen receptor (AR) degradation and increased survival rate, grip strength, and step distance. The study of Kurrat et al. [40] showed that lifelong intake of isoflavone could increase the muscle mass of soleus muscle (M. soleus) and gastrocnemius muscle (M. gastrocnemius) of OVX Wistar rats. As soy isoflavones are known as phytoestrogens, they might cause anabolic effects of estrogens on skeletal muscle mass [42, 43]. Because OVX Wistar rats represent a model of postmenopausal females, soy isoflavones might act as estrogenic compounds to stimulate myosin heavy chain I expression [44]. However, the molecular mechanisms of growing skeletal muscle mass are very complex. More investigation is warranted on growing skeletal muscle mass.

Because the amount of mutant AR is a well-known indicator of SBMA degeneration which is caused by a CAG repeat expansion with the AR gene, downregulation of mutant AR is an important factor for treatment [45, 46]. Studies showed that in an animal model of SBMA, mutant AR was susceptible to genistein treatment, indicating that genistein-mediated down-regulation of mutant AR could reduce motor impairments [45, 46].

Soybean, as a preventive food for sarcopenia

Nutritionally, because sarcopenia is caused by a deficiency in muscle protein, proper protein intake is one of the most important factors in the maintenance of muscle mass [47]. Studies investigating effects of dietary proteins are ongoing [48,49,50]. Healthy eating with proper protein sources is also important for preventing sarcopenia. Animal-based proteins also have a great ability to enhance muscle protein synthesis and plant-based protein sources are rich in fibers and minerals [51, 52]. Nowadays, excessive consumption of meat and meat products is frequently linked to excessive energy and fat accumulation, resulting in obesity, excess weight, and an increased risk of chronic diseases such as fatty liver disease and type 2 diabetes [53]. Therefore, soybean could be a great protein source for preventing muscle loss associated with aging instead of animal proteins today.

Research on soybean isoflavone and muscle loss included in this study showed that soybean isoflavone may prevent myotube atrophy by blocking the expression of MuRF1 or by regulating androgen receptors. Based on research findings, traditional soybean consumption in Korea may have helped prevent sarcopenia, even if soybean was not utilized exclusively to prevent sarcopenia in the local community.

Conclusion

The present study showed the potential of soy isoflavones as preventers of sarcopenia by preventing muscle loss. Consumption of traditional soybean food in Korea could potentially help prevent sarcopenia. Overall studies are presented in Fig. 4. According to the results of this study, soybean consumption helps prevent muscle loss. Therefore, consistent consumption of soybean products may prevent muscle mass from decreasing with age. Further studies for the preservation of muscle by modifying the distribution of protein sources are needed to prevent sarcopenia and maintain health at the same time.

Fig. 4

Overall studies about effect of soybean-derived isoflavone on muscle

Limitations

The present study has several limitations. First, this study did not present remarkably comparable factors among the included studies. Second, the included studies were not enough to suggest other reliable results. More studies of in vitro and in vivo experiments about the relationship between soybean isoflavone and skeletal muscle are needed in the future.