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J Phys Fitness Sports Med, 4(3): 259-270 (2015)DOI: 10.7600/jpfsm.4.259

JPFSM: Review Article

Nuclear receptors and skeletal muscle fiber type

Wataru Mizunoya

Received: April 30, 2015 / Accepted: May 25, 2015

Abstract The contractile and metabolic properties of skeletal muscle depend on muscle fiber type composition. There are two major fiber types: type 1 fibers (slow-twitch oxidative) and type 2 fibers (fast-twitch glycolytic). Muscle fiber type is a critical physiological property that affects sports performance and metabolic ability. To date, natural food components have not been regarded as regulators of skeletal muscle fiber type. Meanwhile, in the present century, it has been revealed that several nuclear receptors (NRs) and their cofactors affect skeletal muscle fiber type independently from muscular contraction. Interestingly, many compounds from natu-ral food sources have been identified as NR ligands. These facts indicate the possibility of the regulation of muscle fiber type by food components. In this review, we present an overview of the current knowledge of the role of NRs and their cofactors in skeletal muscle fiber type and discuss the perspective of muscle fiber type regulation by food components via NR.Keywords : skeletal muscle, fiber type, nuclear receptors, nuclear receptor cofactors, food com-

ponents, myosin heavy chain

Skeletal muscle fiber type and its physiological meaning

Skeletal muscle is composed of thousands of muscle fibers. The contractile and metabolic properties of skel-etal muscle tissue depend on its fiber type composition. There are two major fiber types: type 1 fibers (slow-twitch oxidative, red muscle) and type 2 fibers (fast-twitch gly-colytic, white muscle). Type 1 fibers are rich in mitochon-dria, possess a high oxidative capacity, and are resistant to fatigue. Muscles enriched in type 1 fibers, such as the soleus, perform sustained and tonic contractile activities, such as postural tension. Conversely, type 2 muscle fibers exhibit high glycolytic metabolism and fatigue easily. Muscles enriched in type 2 fibers, such as the extensor digitorum longus (EDL), are typically involved in intense and rapid activities of short duration. In human vastus lateralis muscles collected from a total of 418 Caucasians, the lowest and highest proportion of type 1 fiber were 15 and 85%, and the coefficients of variation (CV) reached approximately 30%1), suggesting a large variation of mus-cle fiber type composition within the population. Overall fiber type composition affects exercise performance, fatigue resistance, and metabolic capacity in humans. Studies in animal models have also demonstrated a strong relationship between muscle fiber type and the develop-ment of diabetes and obesity2,3). Some diseases interfere with the composition or distribution of muscle fiber type, which can be an important clinical manifestation4). Thus,

the elucidation of muscle fiber type regulation may help in understanding human metabolic disorders, exercise performance and skeletal muscle diseases. It is estimated that fiber type composition is regulated both genetically and environmentally (e.g., exercise) almost equally5). Although genetic factors remain largely unknown at pres-ent, here, we focus on an environmental factor. Specifi-cally, we focus on a transcription factor called the nuclear receptor (NR) superfamily, which contributes to fiber type alterations by interacting with various extracellular factors. Fiber type characteristics are determined by cer-tain properties, such as metabolic capacity, mitochondria content, and contractile properties. In this paper, we tried to limit the effect of NR on myosin heavy chain (MyHC) isoform composition, which is the most commonly used protein marker of muscle fiber type. Myosin is a predominant and key component of skel-etal muscle proteins. It is a molecular motor that gener-ates contraction force by consuming ATP. Myosin is an enzyme classified as an ATPase and a hexamer consist-ing of two identical MyHC subunits with four light-chain subunits. The catalytic domain of ATP hydrolysis and interaction with actin exist in MyHC subunits6). To date, four predominant MyHC isoforms have been found in adult mammalian skeletal muscles and identified as MyHC1, 2A, 2X, and 2B7). In general, one muscle fiber (muscle cell) expresses only one MyHC isoform. MyHC1 is expressed in type 1 muscle fibers. Type 2 fibers are further subdivided into type 2A, 2X, and 2B muscle fi-bers, in which MyHC2A, 2X, and 2B are preferentially Correspondence: [email protected]

Department of Bioresource Sciences, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan

260 JPFSM : Mizunoya W

expressed, respectively. Type 2A and 2X fibers have intermediate characteristics between type 1 and type 2B fibers. Although type 2X fibers are sometimes defined as fast-twitch glycolytic fibers, type 2B fibers have an even stronger fast-twitch glycolytic phenotype than type 2X fibers8-10). In human muscles, MyHC2B is not detectable, although the corresponding MyHC2B (MYH4) gene is present in the genome, and fibers typed as 2B based on myosin ATPase staining are in fact 2X fibers based on MyHC composition9).

Nuclear receptors (NRs) overview

The NR superfamily functions to regulate development and reproduction and to coordinate diverse aspects of or-gan physiology. By sensing chemical substances mainly from the extracellular environment, NRs direct a wide range of genetic molecular programs that govern devel-opment, reproduction and metabolism. There are already good reviews about NRs11-13). Here, a brief explanation is described as follows. As its name suggests, a “nuclear receptor” is a receptor that forms molecule complexes with chemical substances called ligands. Typical ligand molecules of NR are fat-soluble hormones, vitamins, and dietary lipids, which are hydrophobic molecules that generally have relatively low molecular weights. Currently, approximately half of NRs are thought to be orphan receptors whose ligands have not been identified. The transcriptional activation by NR is processed as described here: ligands bind to NR, forming a hetero- or homodimer of the NR, which binds to specific regions on the DNA of target genes, and recruit transcription coacti-vators to the ligand binding domain of NR, regulating tar-get gene expression. An especially important trait of NR is the transfer of information from the extracellular envi-ronment toward gene expression and genetic programs of target cells directly. The way to reflect extracellular in-formation into the cellular genetic program of NR is quite different from that of transmembrane receptors, such as G protein-coupled receptors (GPCR). NR can bind DNA directly in the nucleus and acts as a type of transcrip-tion factor. This process is in contrast to transmembrane receptors, which utilize many complicated intracellular signaling pathways. It is very difficult to depict overall pathways of signal transduction of transmembrane recep-tors, because complicated interactions among signaling molecules of multiple pathways occur in the cells until the final output, which modifies the genetic program. The mechanism of transcriptional control by NRs is a rela-tively simple pathway. Currently, 49 mouse NRs and 48 human NRs have been identified, in which the human farnesoid X receptor (FXR) gene is known as a pseudogene located on chromosome 114). Yang et al. investigated the expression of NRs in the four key metabolic tissues. As a result, they found that the

number ranged from 37 in skeletal muscle to 42 in white adipose tissue15). Focusing on the skeletal muscle, ap-proximately one sixth of 37 NRs were related to circadian rhythm. Although the functions and significance of circa-dian rhythm and NRs are not well understood, the pattern must be related to various physiological aspects that have circadian rhythm. Thus, the fact that these 48 or 49 NRs have different expression patterns for each tissue suggests that differ-ent transcriptional control by NRs for each tissue exists. Furthermore, it is possible that the target genes could differ for each tissue even in the same NR because genes are differentially expressed across tissue types and de-velopmental stages to acquire specific tissue or cell traits (e.g., unique contractile proteins of skeletal muscle). As transcription factors, it is known that NRs regulate mul-tiple genes in our cells. However, little is known about how such specific genes to specific tissues are included in these target genes of NR. ChIP assays using specific antibodies to specific NRs using cultured cells will reveal target genes of the NR in that type of cell; however, it is not guaranteed that target genes are identical in any type of cell. For example, Adhikary et al.16) showed that some genes are inducible by peroxisome proliferator-activated receptor δ (PPARδ) agonists in cells, such as IMPA2 in diploid human fibroblasts17) or HMOX1 in endothelial cells18), but are not inducible in WPMY-1 myofibroblast stromal cells. The authors also showed that PDPK1 and ILK genes, which are ligand-inducible in mouse keratino-cytes19), are unresponsive to ligand in WPMY-1 cells. Different stages of differentiation of tissue or cells have different chromatin structure and different levels of DNA methylation. This molecular difference in chromosome and DNA is the basis of epigenetic transcriptional control. Similarly, the interaction of NR and DNA should also be significantly affected by the epigenetic condition, which is not fully understood. For this reason, we cannot deter-mine NR activity and target genes using only the specific sequences of DNA called hormone response elements (HREs).

NR and skeletal muscle fiber type

NRs modify genetic programs of many physiological events, and skeletal muscle fiber type is not an exception. To date, gain- or loss-of-function studies in some NRs re-vealed significant fiber type alterations in mice. We pres-ent, in this section, the studies of NRs relating to skeletal muscle fiber types, especially focusing on MyHC regula-tion.

Peroxisome proliferator-activated receptor δ (PPARδ). Peroxisome proliferator-activated receptors (PPAR) are NRs that have the three family members, PPARα, PPARγ and PPARδ. PPARs have originally been shown to regu-late lipid metabolism and energy homeostasis by coor-

261JPFSM : Nuclear receptors and fiber type

dinated actions in adipose tissue, liver, and muscle. Cur-rently, among the three PPAR family members, PPARδ is believed to be the key NR and the most studied NR for regulating muscle fiber type. A pioneering report using PPARδ transgenic mice was published by the Evans’s group in 2004. Overexpression of constitutively active, muscle-specific VP16-PPARδ enhanced mitochondrial gene expression in association with a fiber type shift from fast glycolytic type 2 fibers to slow oxidative type 1 fibers in mice3). The authors used the metachromatic staining method to evaluate skeletal muscle fiber types of mice, in which densely stained fi-bers are considered to be type 1 fibers. Although the fast-to-slow fiber transition sometimes concomitantly occurs in a type 2B-to-type 2X/2A (fast-to-intermediate) transi-tion, this type of transition was not obvious in these trans-genic mice. Although the metachromatic staining should distinguish between type 1, 2A, 2X and 2B by staining intensity, the difference among type 2 fibers appeared subtle in the published images. In correspondence with an increase of type 1 fibers, the PPARδ-transgenic mice could continue running up to twice the distance of a wild-type littermate. Luquet et al. also produced a muscle spe-cific PPARδ (native form) overexpression mouse20). These mice also showed the fast-to-slow transition. They indi-cated this alteration by succinate dehydrogenase (SDH) staining, in which SDH positive fibers included type 2A fibers and type 1 fibers. SDH positive fibers of this mouse must be type 1 fibers when considering the result of the metachromatic staining by Wang et al. These histological observations were confirmed by an increase in oxidative enzyme expression, such as carnitine palmitoyltransferase 1 or cytochrome c oxidase II. The subsequent study by Gan et al. revealed that muscle-specific overexpression of PPARδ increased MyHC1 composition and decreased all MyHC2 isoforms in the soleus and gastrocnemius using the myosin ATPase and immunostaining method, indicat-ing that PPARδ induces a type 2-to-type 1 transition. Conversely, Schuler et al. reported that the muscle-spe-cific PPARδ-null mice have a reduced oxidative capacity and mitochondrial gene expression in muscle2). They used histochemical staining of NADH-tetrazolium reductase (NADH-TR), a marker of mitochondrial respiratory chain complex I activity. NADH-TR staining showed a similar pattern to SDH staining. The NADH-TR positive fibers were type 2A and 1. The knockout of muscle PPARδ induced a type 1-to-type 2 transition, which is opposite of the overexpression of PPARδ. They also found a sig-nificant decrease in the mRNA levels of the slow MyHC1 and an increase in the fast MyHC2B, which supported the slow-to-fast fiber type transition observed at the transcript level. PPARδ activates transcription by binding to specific re-sponse elements (PPRE) of oxidative enzyme genes. In a preliminary in silico study, Peltzer et al. searched for both HRE and PPRE domains in enhancer regions of MyHC

genes21). Using the Genomatix software, they found cor-responding domains in all MyHC genes. Whether such sequences might be functionally active remains to be elu-cidated. Wang et al. showed that oral administration of the PPARδ-specific agonist GW501516 for 10 days caused an increase in troponin I (slow), which is a type of myofi-brillar protein, and other molecule markers of slow-twitch type approximately doubled compared to the control3). This finding suggested that pharmacological activation of PPARδ can be used to increase slow twitch fibers. Al-though it is estimated that an increase of troponin I (slow) is concomitant with an increase of MyHC1, it is not clear at present whether there is a full correlation. Again, MyHC is a more frequently used marker of muscle fiber type than troponin. However, in fact, there are few reports that examined the MyHC composition after PPARδ ago-nist administration. As one of several examples, Narkar et al. examined the composition in a report in 200822). In that report, fast-to-slow fiber transition by PPARδ agonist administration was effectively and synergistically induced by combining exercise training compared with PPARδ agonist administration alone. The effects of PPARδ ago-nist treatment alone on the expression level of a few oxi-dative metabolism related genes was comparable with the mice treated with both exercise and the PPARδ agonist, suggesting that PPARδ activation works in predominantly oxidative metabolism than in muscle contractile proteins (fiber type marker proteins). Interestingly, a difference in drug reactivity between type 2-dominant and type 1-dom-inant muscles has been also observed in PPARδ agonist (GW501516)-treated animals in that report. The authors described that in all of their gene expression studies, the maximal effects of PPARδ activation were predominantly detected in fast-twitch (quadriceps and gastrocnemius) and not slow-twitch (soleus) muscles. This result means that PPARδ regulation is different in each skeletal muscle tissue based on muscle fiber type composition and sug-gests that PPARδ has already been sufficiently activated in slow-twitch fibers. There are some investigations regarding the contribution of other PPAR isoforms in skeletal muscle fiber types. Previous reports using PPARα knockout mice clearly indicate that PPARα plays an obligatory role in regulat-ing lipid homeostasis in the liver and heart23). However, exercise- and starvation-induced regulation of pyruvate-dehydrogenase kinase 4 (PDK4) and uncoupling protein 3 (UCP3) was similar in the skeletal muscle of wild-type and PPARα knockout mice24). In contrast, muscle-specific transgenic overexpression of PPARα results in a rather reduced capacity for endurance exercise25). Collectively, PPARα and PPARδ share genes relating to lipid metabo-lism, but do not share genes related to skeletal muscle fi-ber type and overall muscle performance. PPARγ is most abundant in adipose tissue, where it activates transcrip-tional programs for lipid storage and lipogenesis26). The


very low expression level of PPARγ in muscles suggests that this subtype does not play a major role in regulating fatty acid metabolism24,27,28). However, thiazolidinedione (TZD), a PPARγ-specific agonist, administration resulted in a small increase in fatty acid metabolism-related genes in the skeletal muscle of rats, suggesting a slight meta-bolic regulatory role for PPARγ in skeletal muscles29).

Estrogen receptor-related receptor γ (ERRγ). ERRγ, unlike ERRα and β, is more selectively expressed in met-abolically active and highly vascularized tissues, such as heart, kidney, brain and skeletal muscles30-32). In skeletal muscles, ERRγ is expressed at high levels in the soleus (type 1 dominant) and at low levels in the EDL (type 2 dominant). Muscle-specific VP16-ERRγ transgenic mice demonstrated a robust increase in SDH positive fibers (type 1 or type 2A fibers) in the tibialis muscle33). The de-crease in mRNA expression of MyHC2B and a concomi-tant increase in the expression of MyHC2X and MyHC2A indicate a type 2B-to-type 2X (2A) transition by ERRγ activation. These mice also demonstrated an increase in exercise capacity, mitochondrial enzyme activity, and enlarged mitochondria despite lower muscle weights. In contrast, ERRγ-deficient mice exhibited a decreased exer-cise capacity and muscle mitochondrial function. Narkar et al. also produced ERRγ-transgenic mice and found a similar phenotype in these mice34). However, these mice showed a significant increase in MyHC1 mRNA expres-sion in the quadriceps muscles. It is possible that the genetic program can be slightly different among different skeletal muscle tissues. Recently, it has been suggested that the microRNA (miRNA) network is responsible for the downstream reg-ulatory mechanism by PPARδ and ERRγ activation, link-ing muscle fiber types25). Gain-of-function and loss-of-function strategies in mice, together with an assessment of muscle biopsies from humans, demonstrated that the type 1 muscle fiber proportion is increased via the stimulatory actions of PPARδ and ERRγ on the expression of miR-499 and miR-208b. Nevertheless, the difference in the fi-ber type transition between PPARδ- and ERRγ-transgenic mice remains inconclusive as these NRs are considered to regulate the same miRNAs.

Thyroid hormone receptor (TR). Thyroid hormone receptors are most likely the first known NR to affect skeletal muscle fiber type. Originally, researchers found that hypo- or hyperthyroidism affected skeletal muscle fiber type35-38). In hypothyroidism, type 2 fibers are con-verted to an oxidative type 1 fiber39,40). Thyroid hormone injection induces a consecutive shift from MyHC1 to 2A, 2X, and 2B38,41). It is widely accepted that the action of thyroid hormone is mainly mediated through the thyroid hormone receptor (TR). Mammalian TRs are encoded by two genes, designated as TRα and TRβ. Furthermore, the primary transcript for each gene can be alternatively

spliced, generating different alpha and beta receptor iso-forms. Currently, four different thyroid hormone receptors are recognized: TRα1, TRα2, TRβ1 and TRβ2. Yu et al. have reported that lack of the TRβ gene has no significant effect on the MyHC composition evaluated by electrophoretical analyses and myosin ATPase staining for soleus and EDL, and that an increase of MyHC1 occurs in TRα1-deficient muscle, suggesting a major role for TRα1 in the phenotypic determination of skeletal muscle fibers42). Interestingly, this study demonstrated a more pronounced type 2-to-type 1 fiber type transition in TRα1/β-double-deficient mice compared with TRα1-deficient mice. These results indicate that TRβ could potentiate the actions of TRα1. Similar to PPARδ and ERRγ, the miRNA network seems to regulate the muscle fiber type through TR. Zhang et al. found that the inhibition of miR-133a re-sulted in an attenuation of the effect of thyroid hormone on muscle fiber determination both in vitro and in vivo43). Mechanistically, they demonstrated that miR-133a regu-lates a slow-to-fast muscle fiber type transition by tar-geting TEA domain family member 1 (TEAD1), a key modulator of the slow muscle gene. Thus, miRNA seems to be a key messenger of NR in terms of muscle fiber type regulation.

NR4A orphan nuclear receptors. In mammals, the NR4A subgroup consists of three closely related orphan NRs: neuron-derived clone 77 (Nur77/NR4A1), nuclear receptor-related 1 (Nurr1/NR4A2), and neuron-derived orphan receptor 1 (Nor-1/NR4A3). Chao et al. previously showed that Nur77 regulates the expression of a battery of glucose utilization genes in fast-twitch muscle fibers and believed that Nur77 increased fast-twitch fibers44). In contrast, their later research revealed that Nur77-overexpressing muscle had a higher expression of tro-ponin I (slow) and MyHC1, two markers of slow-twitch skeletal muscle fibers and a lower expression of troponin I (fast) and MyHC2B45). Interestingly, the change in fiber type composition was more pronounced in muscles that contain mixed fiber types, such as the gastrocnemius and plantaris, and less apparent in muscles that are predomi-nantly fast-twitch and glycolytic in nature. Metabolomic analysis confirmed that Nur77 transgenic muscle favored fatty acid oxidation over glucose oxidation, mimicking the metabolic profile of fasting. The Nur77 overexpres-sion induced no difference in the expression of MyHC2A and 2X, indicating the specific regulation of MyHC1 and 2B by Nur77. Surprisingly, in the global or muscle-specific Nur77-deficient mouse, only the smaller myofi-bers in all four fiber types of the gastrocnemius muscle were affected and no alterations in muscle fiber type were induced46). Pearen et al. developed a mouse model with preferen-tial expression of activated Nor-1 in skeletal muscle47). In quadriceps and gastrocnemius muscles, this resulted in


significantly increased MyHC2A, 2X mRNA and protein and decreased MyHC2B mRNA and protein. The unique effect of Nor-1 overexpression induced a reduction of MyHC1, not only MyHC2B. Despite the decrease of slow type 1 fibers, the Nor-1 transgenic line displayed signifi-cant improvements in the oxidative capacity of skeletal muscle and running endurance, most likely by dominant fast-twitch oxidative type 2A and 2X fibers. Thus, the NR4A subgroup seems to play a very important role in regulating skeletal muscle fiber type. The function of Nurr1 in skeletal muscle is expected to be revealed in the near future.

Androgen receptor (AR). In general, androgen is well recognized as an anabolic steroid for skeletal muscle hypertrophy. A recent prominent report demonstrates that supraphysiological doses of testosterone, a major an-drogen, in men, caused skeletal muscle hypertrophy and increased strength. The manipulation of the AR gene also affects skeletal muscle fiber type. Altuwaijri et al. exam-ined muscle fiber type using AR knockout male mice48). They found that AR knockout induced a significant reduc-tion in slow MyHC and troponin I (slow) and an increase in troponin T (fast) by Western blotting of quadriceps, suggesting that AR signaling plays a role in increasing or sustaining slow-twitch fibers and downregulating fast-twitch fibers.

Other NRs. The REV-ERB-α protein is a key regula-tory component of the circadian clock and is highly ex-pressed in skeletal muscle. A 50% increase in MyHC1 and decrease in MyHC2A from REV-ERB-α homozy-gous knock-out mice was observed without a significant change in soleus muscle mass, suggesting a role for REV-ERB-α in muscle fiber type regulation to some extent49). Glucocorticoid receptor (GR) is involved in inflamma-tory responses, cellular proliferation, and differentiation in target tissues. In skeletal muscles, GR levels were rela-tively high in type 2-rich gastrocnemius and tibialis an-terior muscles compared to the type 1-rich soleus muscle in rats. Histological examination of the gastrocnemius muscle demonstrated typical type 2 fiber-dominant atro-phy in the dexamethasone-treated mice, suggesting that GR activation induced type 2-specific atrophy and a fast-to-slow composition shift50). Although this alteration may be different from genetic reprogramming, the total muscle characteristics relating to muscle fiber type would be changed by GR action.

Cofactors of NR and skeletal muscle fiber type

The transcriptional functions of NRs are mediated by cofactors that are broadly defined as coactivators and corepressors based on their requirement for gene tran-scriptional activation or repression. In the most accepted model, when the ligand-binding domain of NR is bound

to an agonist, the NR disassociates from a corepressor and is able to recruit and bind to a coactivator. Therefore, the NR transcriptional activities significantly rely on these cofactors. Again, gain- or loss-of-function studies reveal new functions regarding these cofactors. Though genetic modification of cofactors showed extensive alterations in skeletal muscle fiber type, this phenotype must be a result from an alteration of NR activities that affect skel-etal muscle fiber type, such as PPARδ. To date, the actual partners (i.e., NRs or possibly other transcription factors) of these cofactors in the nuclei and cells remain to be elucidated because these cofactors are thought to interact with several NRs and work as multiple regulators. Thus, we assume that the quantitative balance of cofactors and NRs together with ligand activation will give a final out-put of a genetic program. To understand the correct mech-anism of NRs, we must reveal the expression pattern, levels and affinity between all NRs and cofactors. In fact, more complicated regulation must exist because these cofactors interact with various other general transcription factors and there must be posttranslational modifications.

Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α). PGC-1α is a transcriptional coactivator that was first discovered by Spiegelman’s group as a cold-inducible protein that binds to PPARγ and increases the expression of UCP1 in the brown fat of mice51). They showed that PGC-1α is a potent transcrip-tion coactivator for NRs and certain other transcription factors52). In 2002, they published a very impressive re-port that revealed the potent effect of PGC-1α on skeletal muscle fiber type and energy metabolism53). Their critical findings in this article were that (i) PGC-1α is expressed preferentially in muscles rich in type 1 fibers, such as the soleus, and (ii) forced expression of PGC-1α in muscles rich in type 2 fibers (plantaris muscle) evokes marked changes in muscle morphology, gene expression and func-tion, triggering the formation of type 1 and type 2A fibers assessed by metachromatic and immunological staining. In this report, they mentioned that a role for PGC-1α in stimulating the expression of myofibrillar proteins char-acteristic of type 1 muscle is entirely unanticipated. Since this publication, in most recent studies related to skeletal muscle energy metabolism, PGC-1α is measured as a master regulator of the muscle cellular metabolic pro-gram.

PGC-1β. PGC-1β was later identified by homology to PGC-1α. Arany et al. (Spiegelman’s group) found that overexpression of PGC-1β caused a marked induction of type 2X fibers in muscles rich in type 2 fibers54). Here, we must note that type 2X fibers (MyHC2X positive fi-bers) are basically categorized as fast-twitch glycolytic fibers, but have slow-twitch characteristics compared to type 2B fibers. Interestingly, PGC-1β transgenic muscle fibers are rich in mitochondria and are highly oxidative.


corepressor protein that binds to the AF2 domain of NRs. In skeletal muscles, RIP140 is expressed abundantly in muscles rich in type 2 fibers58). The absence of RIP140 induced a type 2B-to-type 2X/2A transition in EDL muscles. In contrast, the overexpression of RIP140 in the soleus muscle caused a marked decrease in SDH activity and myoglobin mRNA levels, though the data of MyHC composition were not shown58).

Summary of NRs and NR cofactors that affect muscle fiber type. The above-mentioned corepressors had an opposite role compared to coactivators, such as PGC-1α, in skeletal muscle fiber type regulation, though a slight difference in MyHC isoform regulation still exists in each cofactor. These slight differences were also observed in the effect of NRs on muscle fiber type. When the transi-tion from fast-twitch toward slow-twitch fiber occurs, the metabolic genes and mitochondria markers are upregu-lated, and vice versa. Nevertheless, the MyHC isoform transition pattern is slightly different in respective NRs and NR cofactors (Fig. 1).

Consequently, the transgenic mouse phenotype was very similar to PGC-1α transgenic mice, although the MyHC pattern was completely different. These results suggest that the regulation of metabolic genes is independent of myofibrillar proteins, and the metabolic program seems to be strongly affected by NR or cofactor modifications.

Nuclear receptor corepressor 1 (NCoR1). The NCoR1 is a ubiquitously expressed corepressor, originally identi-fied as the mediator of ligand-independent transcriptional repression of the thyroid hormone and the retinoic acid receptor55). Yamamoto et al. developed NCoR1 muscle-specific knockout mice, which exhibited a significant increase in type 2A and 2X fibers in gastrocnemius and quadriceps muscles evaluated by immunohistochemistry and qRT-PCR56). Interestingly, later research demonstrated that global gene expression analysis revealed a high over-lap between the effects of NCoR1 deletion and PGC-1α overexpression on oxidative metabolism in muscle57).

Receptor-interacting protein 140 (RIP140). RIP140 is a

Fig. 1 Schematic model of the roles of nuclear receptors (NRs) and their cofactors in skeletal muscle fiber type regulation. The muscle fiber type was classified according to myosin heavy chain (MyHC) isoforms identified as MyHC1, 2A, 2X,

and 2B from slow to fast-twitch phenotype. This model is depicted by the results of the previously developed overexpres-sion or knockout mouse models. Agonist induced activation of NRs may differ from this model because the phenotype of overexpression models tends to be prominent. Downregulation by NRs is not concisely shown in this scheme. Oxidative metabolism and mitochondrial biogenesis of skeletal muscle are increased in type 2B-to-type 2A/2X transition (by ERRγ, Nor-1 or PGC-1β) as well as type 2-to-type 1 transition. PPARδ: peroxisome proliferator-activated receptor δ, ERRγ: estro-gen receptor-related receptor γ, TRα: thyroid hormone receptor α, Nur77: neuron-derived clone 77, Nor-1: neuron-derived orphan receptor 1, PGC-1α: peroxisome proliferator-activated receptor γ coactivator-1α, PGC-1β: peroxisome proliferator-activated receptor γ coactivator-1β, NCoR1: nuclear receptor corepressor 1, RIP140: receptor-interacting protein 140.


get gene promoters. Furthermore, not only lipophilic compounds, but also peptides are candidate ligands of NRs67). Food-derived biologically active peptides have been found in many dif-ferent foods, and many products containing bioactive pep-tides are already on the market; casein-derived peptides have already been applied as dietary supplements and pharmaceutical preparations. Recently, Marcone et al. re-ported that milk-derived peptides inhibited inflammatory reactions in human endothelial-monocytes, in which this inhibitory effect was completely reversed in the presence of the specific PPARγ inhibitor, GW9662, suggesting that the milk-derived peptide worked as a ligand for PPARγ68). The search for PPARδ agonists from natural products was not strenuously performed in this research field until recently, perhaps due to a delay in the clarification of the physiological function of PPARδ compared to PPARα/γ. At present, several studies revealed PPARδ agonistic activities from plants or mushrooms, including ethanol extract of Artemisia iwayomogi69), secondary metabolites from the roots of Asarum sieboldii70), flavonoids from the roots of Sophora flavescens71), triterpenes and triter-pene saponins from the stem bark of Kalopanax pictus72), diarylheptanoid glycosides from Tacca plantaginea73), γ-mangostin from Garcinia mangostana74), resveratrol and Vaticanol C from the stem bark of Vatica rassak75), and sterol fatty acid esters from the mushroom Hericium erinaceum76). These compounds have sometimes dual or triple agonistic activities against PPARα/γ.

Food components that affect skeletal muscle fiber type. To our knowledge, few studies have been conducted on the effect of nutrients on muscle fiber type transition. Fatty acids are ubiquitous biological molecules that are used as metabolic fuels, covalent regulators of signaling molecules, and essential components of cellular mem-branes. Fatty acids are natural, endogenous ligands for PPARs, and they mediate adaptive metabolic responses to changes in systemic fuel availability. For example, eicosapentaenoic acid (EPA), a typical n-3 polyunsatu-rated fatty acid (PUFA), is a much more potent activator of PPARα in primary hepatocytes than arachidonic acid, an n-6 PUFA77). Using luciferase reporter assays, Forman et al. demonstrated that PUFAs, such as linoleic acid, arachidonic acid, and EPA, are much more potent activa-tors of PPARδ at a concentration of 30 µM78); this level is physiologically relevant because mammalian serum free fatty acid concentrations can be greater than 100 µM. Therefore, it is possible that EPA, which is abundant in fish oil, could function as a PPARδ agonist and affect the expression of contractile and metabolic genes in skeletal muscles. Mizunoya et al. examined whether the continu-ous intake of fish oil rich in EPA affects the muscle fiber types in rats with a 15% fat diet derived from different fat sources79). As a result, compared with soybean oil intake, fish oil intake showed significantly lower levels of the

Perspective of muscle fiber type regulation by food component via NR

NR ligands from natural food sources. Is it possible that NR activity could be affected by natural food compo-nents or nutrients? The answer is entirely positive. NRs are important biological targets of active compounds con-tained mainly in herbal and dietary plants (in this paper, we do not distinguish between food and herbal medicine because both are natural edible materials). This fact is an interesting phenomenon, as NRs might perhaps evolve to be regulated by lipophilic molecules derived from dietary plants as a clue to understanding our body accommoda-tion to ingested food. Previously, Lazar showed that 13 natural compounds purified from herbs could activate 10 NRs, such as ER, PPARα/γ, and AR59). Some compounds listed in that article target multiple NRs, suggesting that many natural compounds are not specific ligands to spe-cific NRs. Furthermore, Goto et al. found that various terpenoids contained in many herbal plants have PPARγ ligand activity60). Recently, Wang et al. summarized many identified PPARγ-activating constituents, mainly from medicinal plants61). Notably, in addition to plants and mushrooms applied in traditional medicines, PPARγ ligands have often been identified in plants that are com-mon food sources, including the tea plant, soybeans, palm oil, ginger, grapes and wine, and a number of culinary herbs and spices. Here, please note that the term “ligands” includes agonists, antagonists and inverse agonists, mean-ing that not all of the compounds induce the activation of NRs. ERRγ, considered to be a non-liganded constitutively acting receptor, can be activated without any agonists. In fact, PGC-1β behaves like an endogenous ERRγ ligand62); however, a true ligand should enhance the interaction be-tween ERRγ and PGC-1β. Constitutive activity does not exclude the existence of a ligand. Indeed, some research-ers found agonists for the ERR subfamily from natural food compounds. In particular, soy isoflavones and their metabolite, equol, stimulated the transcriptional activity of the ERR subfamily and enhanced its interaction with coactivators63,64). Originally, soy isoflavones were found to be structurally similar to estrogen and named as phy-toestrogens in the 1960s, and have a preferential affinity for estrogen receptor-β (ERβ), which is also an NR. REV-ERB-α is also considered to be a non-liganded constitutively active receptor. The 3D structural determi-nation of REV-ERB-α has demonstrated that the putative ligand-binding pocket was actually packed with amino acid side-chains, rendering the entry of a ligand very un-likely65). However, it should be remembered that constitu-tive activity does not exclude the existence of a ligand. Indeed, the activity of this receptor can be regulated by the porphyrin heme66). Heme binds directly to the ligand-binding domain and regulates the transcriptional activity of the REV-ERB subfamily to recruit corepressors to tar-


dative enzyme capacity of skeletal muscle86). Of note, this also causes a decrease in L-carnitine levels in muscles. L-carnitine supplementation helps in recovery from mi-tochondrial dysfunction87). These findings indicate that carnitine supplementation through normalizing carnitine status is able to prevent type 1-to-type 2 transition due to obesity. Actually, carnitine supplementation to obese Zucker rats counteracted the obesity-induced type 1-to-type 2 transition and restored the muscle oxidative meta-bolic phenotype, which were measured by myosin ATPase staining and qPCR88). Further research is needed to test whether carnitine supplementation could induce the type 2-to-type 1 transition in normal animals, and not just pre-vent a slow-to-fast fiber type transition in obese animals. Yoshihara et al. previously investigated the effect of beef extract intake that contains high levels of L-carnitine on rat muscle fiber types89). The muscle fiber type was evaluated by myosin ATPase staining and electrophoreti-cal analyses. The results showed that rats fed beef extract increased in type 1 and 2A fibers and decreased in type 2B fibers in EDL muscles. This finding indicates that a type 2B-to-type 2A/1 transition is induced by the supple-mentation of beef extract. Therefore, carnitine may be one of the candidates of nutritional muscle fiber type transi-tion. In a recent study, fish protein was shown to increase fast-twitch muscle weight and upregulate the gene expres-sion of a fast-twitch muscle-type marker in the muscle90). In this research, young adult rats were fed fish protein or casein as a protein source for 8 weeks. The expression of MyHC1 decreased in the soleus muscle, and the expres-sion of MyHC2B increased in the EDL muscle after fish protein intake. These results implied that both the soleus and EDL muscle underwent a shift to fast-twitch muscle. In addition, the research also demonstrated that the gas-trocnemius muscles were whitened by fish protein intake. This study has two uncommon aspects: (i) the induction of slow-to-fast fiber type transition, and (ii) both the soleus and EDL were affected. Most recently published compounds cause fast-to-slow fiber type transition, and this typically occurs in fast type 2-rich muscle tissues. Al-though the molecular mechanism of fish protein remains unknown, it is possible that bioactive peptides derived from fish protein may act as ligands of some NRs.

Concluding remarks

Until the 20th century, it was generally accepted that muscle fiber type was dominated and affected only by motor nerve stimulation and the subsequent calcium stimulation in muscle cells. In other words, exercise was considered the most important and supreme environmen-tal factor regulating muscle fiber type. However, since the 21st century, many studies have been published show-ing that NRs and NR cofactors have a dramatic effect on muscle fiber type. This fact clearly indicates that there is

fast-type MyHC2B and higher levels of the intermediate-type MyHC2X composition in the EDL as evaluated by quantitative electrophoretical analysis, indicating a type 2B-to-type 2X fiber type transition. Concomitantly, My-HC2X mRNA levels in fish oil-fed rats were significantly higher than those observed in the soybean oil-fed rats. However, it remains to be elucidated whether this effect was induced by PPARδ activation from EPA contained in fish oil. Niacin (also known as vitamin B3 or nicotinic acid) is a low molecular substance, which is categorized as one of the essential human nutrients. At pharmacological doses, niacin exerts pronounced lipid-lowering activities80). With respect to possible further mechanisms underlying the lipid-lowering effect of niacin treatment, it is worth describing that niacin treatment causes many changes in cellular signaling and gene expression of skeletal muscle81), in which the niacin receptor is not expressed. Khan et al. examined the effect of a 750 mg niacin/kg diet supplement for 3 weeks on pig muscle fiber type82). After the supplementation period, the fiber type distribution in different skeletal muscles (M. longissimus dorsi, M. quadriceps femoris, and M. gastrocnemius) was examined by myosin ATPase staining. The results demonstrated that the percentage of type 1 fibers in all three muscles was greater in the niacin group than in the control group, indicating that niacin significantly caused a type 2-to-type 1 transition. Similar results were also obtained from the same group using sheep83). What is the underlying mecha-nism that causes fiber type transition by niacin intake? It has been reported that niacin induces PPARγ protein expression and increases PPARγ transcriptional activity via the activation of the prostaglandin synthesis pathway in a cultured lymphoma cell line84). Therefore, niacin may increase PPARδ expression in muscles or increase pros-taglandin, such as 8(S)-HETE, to function as an endog-enous agonist of PPARδ. The relationship between nutrients and NRs is implied in the above-mentioned substances. However, there are some foods known to affect muscle fiber type, in which the involvement of NRs is unclear. In our opinion, these substances can affect or interact with NRs, but this inter-action has not yet been observed. L-carnitine is a natu-rally occurring amino acid, which is synthesized in the liver and kidneys from two essential amino acids, lysine and methionine. With regard to the relationship between L-carnitine metabolism and muscle fiber type, Constatin-Teodosiu et al. previously demonstrated that an accumu-lation of acetyl-L-carnitine in humans is greater in type 1 fibers than in type 2 fibers after exhaustive, prolonged exercise85). They suggested that the physiological role of L-carnitine is as a buffer agent, neutralizing excess ace-tyl groups occurring during prolonged exercise in type 1 fibers. Meanwhile, the reduced type 1 fiber, by high fat diet-induced obesity, is associated with mitochondrial dysfunction characterized by impaired mitochondrial oxi-


a muscle fiber type regulation pathway independent of exercise. The natural edible compounds that are ligands of NRs have been identified in several studies, especially by Asian researchers. Up to now, only a small number of the active compounds in food have been discovered. We expect more natural NR agonists will be discovered in time. Muscle fiber type is a critical physiological property that affects the metabolic ability of animals, sports per-formance for athletes, and meat quality of livestock. We expect the study of food ingredients altering muscle fiber type via NRs will be prevalent in the future.

Conflict of Interests

The author declare that there is no conflict of interests regarding the publication of this article.

Acknowledgments

This review article was made possible by Grant-in-Aid for Young Scientists (A) from Japan Society for Promotion of Sci-ence (#26712023). The publication was supported in part by the Research Grant for Young Investigators of Faculty of Agriculture, Kyushu University.

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