Abstract
The metabolic roles of mitochondria go far beyond serving exclusively as the major producer of ATP in tissues and cells. Evidence has shown that mitochondria may function as a key regulator of skeletal muscle fiber types and overall well-being. Maintaining skeletal muscle mitochondrial content and function is important for sustaining health throughout the lifespan. Of great importance, β-hydroxy-β-methylbutyrate (HMB, a metabolite of l-leucine) has been proposed to enhance the protein deposition and efficiency of mitochondrial biogenesis in skeletal muscle, as well as muscle strength in both exercise and clinical settings. Specifically, dietary supplementation with HMB increases the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), which represents an upstream inducer of genes of mitochondrial metabolism, coordinates the expression of both nuclear- and mitochondrion-encoded genes in mitochondrial biogenesis. Additionally, PGC-1α plays a key role in the transformation of skeletal muscle fiber type, leading to a shift toward type I muscle fibers that are rich in mitochondria and have a high capacity for oxidative metabolism. As a nitrogen-free metabolite, HMB holds great promise to improve skeletal muscle mass and function, as well as whole-body health and well-being of animals and humans.
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Introduction
The mitochondrion has key roles in cell metabolism. The most important function of this organelle is to oxidize energy substrates and produce ATP via the Krebs cycle and the electron transport system (Joseph et al. 2012; Dai et al. 2013). Additionally, the mitochondria play a critical role in maintaining health via their involvement in regulating skeletal muscle fiber size, metabolism, and function (Russell et al. 2014). Particularly, mitochondria may act as a new mediator of skeletal muscle fiber types (Venhoff et al. 2012). Oxidative capacity of fibers is strongly linked with muscle health and overall well-being (Wenz et al. 2009). The protective effects of enhanced mitochondrial oxidative capacity in disease states, such as obesity and diabetes, are largely ascribed to enhanced mitochondrial content and function (Bazer et al. 2015; Scheffler et al. 2014, Tekwe et al. 2013). An increase in mitochondrial mass and/or number is termed “mitochondrial biogenesis.” Multiple genes expressed in mitochondria, such as silent information regulator transcript 1 (SIRT1), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), may be involved in the regulation of mitochondrial biogenesis and fiber-type transformation (Lin et al. 2002). Therefore, mitochondria in skeletal muscle can improve muscle health and overall well-being through regulating skeletal muscle fiber types and expression of key genes involved in this process.
β-Hydroxy-β-methylbutyrate (HMB), a metabolite of the nutritionally essential branched-chain amino acid (BCAA) leucine (Wu 2013), has been proposed as a nutritional supplement to enhance skeletal muscle mass and strength in both exercise and clinical settings by promoting mitochondrial biogenesis ad fatty acid oxidation (Wilson et al. 2008; Stancliffe 2012). Therefore, this review aims to focus on the relationship between mitochondria and skeletal muscle health, as well as the effects of dietary HMB supplementation on promoting mitochondrial biogenesis and protecting against skeletal muscle loss.
Mitochondria: an overview
Mitochondria are highly organized and dynamic organelles, performing myriad roles in bioenergetics, metabolism, and cell signaling. The primary function of mitochondria is ATP production from the oxidation of energy substrates (fatty acids, glucose, and amino acids) (Dai et al. 2013). The reducing equivalents (NADH and FADH2) generated via the oxidation of acetyl-CoA in the mitochondrial Krebs cycle are oxidized to water via the electron transport system. This biochemical event of oxidative phosphorylation produces most ATP in cells that possess mitochondria. Moreover, mitochondria contain enzymes that are essential for the synthesis of cholesterol and play a key role in amino acid metabolism (Wu 2013). In addition, the controlled generation of reactive oxygen species (ROS) by the mitochondria is crucial for both cell signaling and apoptosis (Hock and Kralli 2009; Stancliffe 2012).
Due to these essential roles of mitochondria, there is a tight regulation of mitochondrial mass and function. In response to physical activity, availability of nutrients, and anabolic hormones, this well-coordinated regulation of mitochondrial dynamics permits mitochondria to fulfill their physiological functions through mitochondrial biogenesis. It is an essential biological process required for growth and development, while meeting energy requirements of the cell (Stefano et al. 2012). Of note, the tight control of mitochondrial biogenesis is mainly through transcriptional regulation, particularly, through the synchronized transcription of mitochondrial genes in both the nucleus and the mitochondria (Poyton and McEwen 1996; Mootha et al. 2003). Given these essential roles of the mitochondria in the cell, it is no surprise that damage to mitochondria ultimately leads to disease (Duchen 2004). Abnormal mitochondrial metabolism or activity is termed “mitochondrial dysfunction.” An increasing body of literature identifies mitochondrial dysfunction as a contributing factor to numerous diseases, including liver disease, cardiovascular disease, obesity, diabetes, cancer, and dementia (Zhang et al. 2003; Duchen 2004; Joseph et al. 2012; Stancliffe 2012). Moreover, the accumulation of mitochondrial damage and the resultant oxidative stress has been regarded as a potential mechanism responsible for aging (Weber and Reichert 2010). Previous studies have demonstrated that mitochondrial biogenesis can ameliorate metabolic disorders and promote longevity by decreasing risk of age-related diseases (Filhiol 2012). Accordingly, maintenance of abundant, functional mitochondria is fundamental to life. Some key genes involved in the regulation of mitochondrial biogenesis play important roles in maintaining abundant and functional mitochondria. Therefore, we will discuss key genes involved in the regulation of mitochondrial biogenesis in more detail below.
Key genes involved in the regulation of mitochondrial biogenesis
In response to a stimulus such as excise or skeletal muscle contractile activity, intracellular Ca2+ and AMP levels increase resulting in the activation of signaling molecules. These signaling pathways converge to promote mitochondrial biogenesis (Fig. 1; Joseph et al. 2012).
PGC-1α
PGC-1α is often regarded as the master regulator of mitochondrial biogenesis because of its ability to stimulate the expression of mitochondrial genes (Hock and Kralli 2009). PGC-1α represents an upstream inducer of genes of mitochondrial metabolism by positively influencing some hormone nuclear receptors and nuclear transcription factors, such as peroxisome proliferator-activated receptor α (PPARα), estrogen-related receptor α (ERRα), and nuclear respiratory factor 1–2 (NRF1–2) (Wu et al. 1999; Huss et al. 2004; Narkar et al. 2008; Scarpulla 2011). There is evidence that expression of PGC-1α in cells is enhanced by dietary supplementation with l-arginine (Fu et al. 2005). NFR-1 induces the expression of a segment of the mitochondrial genome, specifically the genes that encode oxidative phosphorylation components and mitochondrial ribosomal proteins (Virbasius et al. 1993; Scarpulla 2008). Co-activation of NRF1 and NRF2 by PGC-1α also stimulates mitochondrial transcription factor A (TFAM) expression (Wu et al. 1999). TFAM is a nucleus-encoded gene that is partially responsible for the coordinated transcription of the nuclear and mitochondrial genomes such as mitochondrial DNA during mitochondrial biogenesis (Pagliarini et al. 2008; Scarpulla 2008). Moreover, PGC-1α induces oxidative phosphorylation (OXPHOS) genes that involved in the final step of electron transport chain and ATP synthesis, thereby allowing for the complete oxidation of fatty acids to water and CO2 in the mitochondria (Wu et al. 1999; Koves et al. 2005). Thus, PGC-1α coordinates the expression of both nuclear- and mitochondrial-encoded genes in mitochondrial biogenesis (Yan et al. 2011).
Due to its vital role in mitochondrial biogenesis, PGC-1α overexpression in skeletal muscle leads to increased mitochondrial abundance and gene expression, and improved exercise performance (Lin et al. 2002; Calvo et al. 2008). Conversely, PGC-1α null mice show a decrease in mitochondrial gene expression and impaired mitochondrial function (Leone et al. 2005; Arany et al. 2006). Moreover, the PGC-1α activity is regulated by SIRT1 and AMPK, which are activated by an increase in cellular energy needs (Gerhart-Hines et al. 2007; Jager et al. 2007).
SIRTs
The SIRTs (SIRTs; SIRT1–7) are a family of NAD+-dependent enzymes that dynamically regulate mitochondrial function. Mammalian SIRTs belongs to class III histone deacetylates with specific subcellular localization and protein substrates (Rodgers et al. 2008). The enzymatic activity of the SIRTs is dependent on the NAD+/NADH ratio and is associated with cellular energy charge (Feldman et al. 2012). Function of SIRT1 is required for the stimulation of mitochondrial biogenesis in skeletal muscle (Price et al. 2012). Moreover, SIRT1 promotes mitochondrial biogenesis via deacetylation and, therefore, activation of PGC-1α (Rodgers et al. 2005; Gerhart-Hines et al. 2007).
Apart from SIRT1, SIRT3 and SIRT5 are also implicated in regulating mitochondrial function. Previous studies have shown that SIRT3 controls the global acetylation status of mitochondrial proteins, increases cellular ATP levels, and induces mitochondrial biogenesis. Moreover, PGC-1α has been reported to induce expression of SIRT3 in an ERRα-dependent manner (Lombard et al. 2007; Ahn et al. 2008; Hirschey et al. 2010; Kong et al. 2010). Recently, SIRT5 has also been identified as a novel factor that controls mitochondrial function (Buler et al. 2014). Overexpression of PGC-1α in mouse primary hepatocytes increases SIRT5 mRNA expression (fourfold) and its protein abundance in a PPARα- and ERRα-dependent manner. Additionally, SIRT5 is also under the modulation of AMPK, but in the opposite direction of PGC-1α. Overexpression of SIRT5 promotes ATP synthesis and oxygen consumption in HepG2 cells, but does not influence mitochondrial mass. Thus, SIRT5 may have a positive effect on oxidative phosphorylation (Buler et al. 2014). Overall, during mitochondrial biogenesis, SIRT1 induces the activation of PGC-1α that is pivotal to orchestrate the activation of a broad set of transcription factors and nuclear hormone receptors, leading to enhanced expression of the nucleus-encoded mitochondrial genes (Aquilano et al. 2010).
AMPK
AMPK is another key factor that mediates mitochondrial biogenesis and is a key element in maintaining energy homeostasis. AMPK responds to AMP, and hence it is sensitive to even discrete changes in cellular charge (Lage et al. 2008; Hardie et al. 2012). Apart from AMP, AMPK (Thr-172) can be phosphorylated and activated by a rise in intracellular Ca2+ via the Ca2+-activated kinase calmodulin-dependent kinase kinase-β (CaMKKβ). Compound C, an inhibitor of AMPK, markedly suppresses leucine’s effects on mitochondrial biogenesis, suggesting that AMPK is required for elevated mitochondrial biogenesis and fatty acid oxidation by leucine in C2C12 myotubes (Liang et al. 2014). There is ample evidence indicating that AMPK can promote mitochondrial biogenesis and oxidative capacity, and prevent the mitochondrial dysfunction in skeletal muscle (Canto et al. 2009, 2010). AMPK might serve as a downstream target of SIRT1. SIRT1 activation is essential for AMPK phosphorylation and improvement of mitochondrial function via deacetylation and activation of liver kinase B1 (LKB1). LKB1 directly phosphorylates Thr-172 of AMPK and activates its kinase activity (Shaw et al. 2004). Thus, it raises the possibility that AMPK might also serve as a downstream target of SIRT1 (Price et al. 2012; Liang et al. 2014). Conversely, AMPK may activate SIRT1 through indirectly increasing cellular NAD+ levels (Canto et al. 2009). Collectively, activated AMPK and SIRT1 further activate PGC-1α through phosphorylation and deacetylation mechanisms, promoting mitochondrial biogenesis and oxidative capacity and preventing mitochondrial dysfunction in skeletal muscle (Jager et al. 2007; Canto et al. 2010).
Taken together, PGC-1α, SIRT1, and AMPK are all involved in the regulation of mitochondrial biogenesis. Their function and regulation are closely intertwined. SIRT1 activates AMPK via deacetylation and activation of LKB1, whereas AMPK activates SIRT1 through indirectly increasing cellular NAD+ levels. Activated SIRT1 and AMPK further activate PGC-1α through phosphorylation and deacetylation, leading to stimulate the expression of mitochondrial genes. In addition, PGC-1α induces the expression of SIRT3 and SIRT5 in a PPARα- and ERRα-dependent manner. Consequently, mitochondrial biogenesis and oxidative capacity within the cell are enhanced.
Mitochondrial function and skeletal muscle health
Skeletal muscle and its fiber type
Lean body mass (LBM) accounts for almost 75 % of normal body weight, and includes all tissues except adipose tissue (Demling 2009). Skeletal muscle comprises the majority of LBM, the maintenance of which is important for supporting whole-body protein metabolism, physical strength, wound healing, immune function, and organ function (Wolfe 2006; Demling 2009). Naturally, a progressive loss of skeletal muscle mass (also known as sarcopenia) occurs with aging. However, injury or/and illness (such as infection, AIDS, cancer, non-healing wounds, and congestive heart failure) can lead to or accelerate this loss of LBM (Hou et al. 2015a; Lin et al. 2002; Demling 2009; Kim et al. 2010; Yi et al. 2015). Besides a loss of skeletal muscle, the sarcopenic phenotype is often linked with a shift in muscle fiber type, a reduced ability to perform activities of daily living, and an increased morbidity and mortality regardless of age (Johnston et al. 2008; Kim et al. 2010). Previous studies have demonstrated that sarcopenia leads to an approximately 50 % reduction in the number of total muscle fibers between the ages of 20–80, accompanied by a disproportionate loss of fast-twitch muscle fibers (Verdijk et al. 2010; Drey 2011).
In mammals, skeletal muscle is a mosaic of different types of muscle fibers with diverse structural properties and functional capabilities. Functional and phenotypic diversity of skeletal muscle is attributed to the heterogeneous composition of fibers (Scheffler et al. 2014). Traditionally, muscle fibers have been classified by immunofluorescence analyses of myosin heavy chain (MHC) isoforms. Based on the expression of the predominant MHC isoforms, humans have three fiber types (I, IIa, and IId/x), while rodents have four fiber types (I, IIa, IId/x, and IIb) (Smerdu et al. 1994; Ennion et al. 1995; Horton et al. 2001; Yan et al. 2011). Type I slow-twitch, oxidative fibers are slow in force generation and have a high capacity for oxidation of energy substrates. These muscle fibers are rich in oxidative enzymes, mitochondria, and capillary (Prince et al. 1981). Type IIa fast-twitch, oxidative fibers are fast in force generation but have similar oxidative profiles to type I fibers (Eddinger and Moss 1987). Type IId/x fibers, which are fast-twitch muscle fibers with a glycolytic metabolic profile, are rich in glycolytic enzymes but poor in mitochondria and capillary blood supply (Prince et al. 1981). Type IIb fibers have an even more fast-twitch, glycolytic phenotype than type IId/x fibers (Termin et al. 1989; Rivero et al. 1998). Muscle fibers are now commonly distinguished as slow-twitch (red) and fast-twitch (white) (Zierath and Hawley 2004). The slow-twitch myofibers contain mainly the type I MHC isoform, which are characterized by the high content of mitochondria and high rates of oxidative metabolism. The fast-twitch myofibers contain type IIa, IId/x, and IIb MHC isoforms, which are mainly glycolytic and perform quick contractions. These muscle fibers are required for movements involving strength and speed, but are easily fatigued (Berchtold et al. 2000; Olson and Williams 2000; Pette and Staron 2001). Each skeletal muscle fiber contains several hundred to several thousand myofibrils which comprise large polymerized protein molecules (actin and myosin) responsible for contraction (Karagounis and Hawley 2010). A shift in fiber distribution from slow-twitch to fast-twitch results from altered activities of key oxidative and glycolytic enzymes (Pette and Hofer 1979; Lin et al. 2002).
Mitochondrial function as a new mediator of skeletal muscle fiber type
Skeletal muscle fiber-type phenotype is mediated by several independent signaling pathways. These include pathways involved with PGC-1α (Lin et al. 2002), calcium/calmodulin-dependent protein kinase (CaMK) (Wu et al. 2002), calcineurin (Naya et al. 2000), and the ras/mitogen-activated protein kinase (Murgia et al. 2000). This review will mainly focus on PGC-1α. In response to mitochondrial dysfunction, skeletal muscle changes fiber-type composition via decreasing the proportion of slow fibers and increasing fast fibers. This transformation in the absence of fiber-type regeneration and observed adjustments from oxidative to glycolytic metabolism provides evidence for mitochondrial function as a new mediator of skeletal muscle fiber type (Venhoff et al. 2012). These authors demonstrated, for the first time, an important role for mitochondrial function in muscle fiber-type transformation. As stated above, PGC-1α plays a particularly robust role in mitochondrial biogenesis and function. It is interesting to speculate that PGC-1α might promote mitochondrial biogenesis and function, leading to increased oxidative capacity of fibers and up-regulated proportion of slow muscle fibers.
Much evidence shows that PGC-1α is a key regulator of fiber-type determination (Gouspillou et al. 2014). It is noteworthy that PGC-1α is expressed preferentially in skeletal muscles rich in type I fibers. Elevation of PGC-1α expression in skeletal muscles rich in type II fibers results in marked changes in tissue morphology, gene expression, and function (Lin et al. 2002). In skeletal muscles, PGC-1α has been reported to cause a shift toward type I fibers that are rich in mitochondria and highly oxidative. Of note, type I fibers contain a high mitochondria content and use oxidative metabolism as a primary source of energy (Lin et al. 2002; Rasbach et al. 2010). Further evidence shows that the beneficial effects of resveratrol on skeletal muscle are likely due to PGC-1α-mediated increases in mitochondrial biogenesis and a shift toward more oxidative muscle fibers (Price et al. 2012). Moreover, muscle-specific PGC-1α knock-out mice show a shift from oxidative type I and IIa toward type IIx and IIb muscle fibers, increasing muscle damage (Handschin et al. 2007). Intriguingly, SIRT1 transgenic muscle exhibits a fiber shift from fast-to-slow-twitch, increases expression of PGC-1α and decreases expression of genes associated with muscle atrophy (Chalkiadaki et al. 2014). The mechanisms whereby PGC-1α promotes a shift toward type I fibers are as follows. PGC-1α serves as a target downstream for calcium/calcineurin/CaMK signaling. CaMK signaling induces PGC-1 expression at a transcriptional level (Lin et al. 2002; Wu et al. 2002). Nfat and myocyte enhancer factor 2 (Mef2) transcription factor families are the two known effectors of the calcineurin signaling on gene expression in skeletal muscle. Moreover, a slow fiber-specific element of the slow troponin l gene contains a canonical Nfat site that is essential for maximal expression in slow-twitch muscle fibers and for maximal responsiveness to calcineurin (Calvo et al. 1999; Wu et al. 2000, 2001). PGC-1α directly interacts with Mef2, which physically binds the Nfat site in a slow fiber-specific element of the slow troponin l gene, increasing expression of type I fibrillar proteins. Consequently, the proportion of slow-twitch fibers is enhanced (Wu et al. 2001; Crabtree and Olson 2002; Lin et al. 2002; Gouspillou et al. 2014).
Taken together, mitochondria regulate muscle fiber-type transformation via PGC-1α (Fig. 2). On one hand, PGC-1α mediates mitochondrial biogenesis and activates oxidative metabolism, driving fast-to-slow fiber switch. On the other hand, PGC-1α directly interacts with Mef2, which physically binds the Nfat site in a slow-twitch fiber-specific element of the slow troponin l gene, increasing the expression of type I fibrillar proteins. Accordingly, the proportion of slow-twitch fiber types is up-regulated, and muscular atrophy is prevented, when PGC-1α is activated.
Mitochondrial biogenesis improves skeletal muscle health
Skeletal muscle plays a major role in oxidizing fatty acids and glucose into water and CO2 (Jobgen et al. 2006). Oxidative capacity of fibers is strongly linked with skeletal muscle health and overall well-being. Enhanced oxidative capacity attenuates muscle loss during aging (Wenz et al. 2009), and affords protection against insulin resistance and metabolic dysregulation (Wang et al. 2004; Scheffler et al. 2014). The protective effects of enhanced oxidative capacity in disease states are largely ascribed to enhanced mitochondrial content and increased mitochondrial function. To accomplish this, mitochondria possess an increased ability to oxidize fatty acids and glucose, augmenting ATP generation and protecting against cellular stress (Scheffler et al. 2014). Therefore, augmenting the proportion of slow-twitch oxidative muscle fibers can improve health via increasing the mitochondrial function and ameliorating metabolic syndrome (Zierath and Hawley 2004). Indeed, the function of skeletal muscle highly depends on the ATP production by mitochondria (Verdijk et al. 2010). As noted previously, mitochondria play a critical role in influencing skeletal muscle fiber size and number to modulate substrate metabolism and the concentrations of lipids and glucose in plasma (Russell et al. 2014). Furthermore, sarcopenic muscle is associated with mitochondrial dysfunction (Johnston et al. 2008; Verdijk et al. 2010; Drey 2011). Accordingly, maintaining mitochondrial content and function of skeletal muscle is of great importance for sustained health throughout the lifespan.
Mitochondrial activity and function in skeletal muscle is a highly controlled process (Joseph et al. 2012). Mitochondrial dysfunction can result in a lowered mitochondrial mass and oxidative capacity, resulting in an increase in free radical production and consequently oxidative stress (Johnston et al. 2008; Verdijk et al. 2010). Impaired mitochondrial function is characterized by a rapid onset of symptoms commonly seen in the elderly, including muscle loss and insulin resistance (Wallace 2010; Sahin et al. 2011). Numerous studies have shown that a decline in mitochondrial function in normal individuals underlie many common age-related diseases and that treatments aimed at stimulating mitochondrial function can delay the progression of some of these diseases (Figueiredo et al. 2009; Wenz et al. 2009; de Moura et al. 2010; Fillmore et al. 2010; Horvath et al. 2011). Therefore, changes in mitochondrial content and function can directly or indirectly impact skeletal muscle function and consequently whole-body health and well-being. Thus, identifying compounds that can attenuate both the mitochondrial dysfunction and the loss of LBM associated with sarcopenia is a key focus of current medical research.
HMB promotes mitochondrial biogenesis and improves skeletal muscle health
The role of HMB in mitochondrial biogenesis
Branched-chain amino acids have been suggested as potential candidates in promoting survival via regulating mitochondrial function (Valerio et al. 2011). For example, leucine can stimulate protein synthesis in skeletal muscle (Davis et al. 2010) and muscle bass (Columbus et al. 2015; Sun et al. 2015). Of note, long-term dietary supplementation with a specific BCAA-enriched mixture (BCAAem) improves age-related disorders in animals and humans and promotes mice survival (D’Antona et al. 2010). The anti-aging role of BCAAs may be mediated by mitochondrial biogenesis in mammals. Specifically, supplementation of BCAAem increases mitochondrial biogenesis and SIRT1 expression in skeletal muscle, and this is accompanied by enhanced expression of ROS-removing genes and reduced ROS production in middle-aged mice (D’Antona et al. 2010). All of the BCAAem-mediated effects are strongly attenuated in endothelial nitric oxide synthase null mutant mice (Pansarasa et al. 2008; Solerte et al. 2008; D’Antona et al. 2010), as physiological levels of nitric oxide are an activator of mitochondrial biogenesis (McKnight et al. 2010).
Of all the BCAAs, leucine is the most effective in the regulation of many cellular processes such as protein synthesis and energy metabolism, and has received much attention (Yin et al. 2010; Li et al. 2011; Duan et al. 2015a, b, c). Recently, increasing evidence has shown that leucine also plays a critical role in mitochondrial biogenesis (Li et al. 2012). In C2C12 cell models, leucine (0.5 mM) increases mitochondrial mass by 30 %, and stimulates expression of mitochondrial biogenesis genes (SIRT1, PGC-1α, and NRF-1) as well as mitochondrial component genes (UCP3, COX, and NADH) by three- to fivefold (Li et al. 2012). Of great importance, SIRT1 has been shown to be implicated in leucine-induced mitochondrial biogenesis in muscle cells, because transfection of C2C12 myocytes with SIRT1 siRNA leads to parallel inhibition of SIRT1 expression and leucine-stimulated activation of PGC-1α and NRF-1 (Sun and Zemel 2009). Likewise, Vaughan et al. (2013) reported that leucine (0.1–0.5 mM) dose-dependently enhanced PGC-1α expression, mitochondrial density, and oxidative capacity in skeletal muscle cells. Further evidence suggests that leucine (0.5 mM) markedly increases mitochondrial content, expression of mitochondrial biogenesis-related genes, fatty acid oxidation, SIRT1 activity and expression, and AMPK phosphorylation in C2C12 myotubes (Sun and Zemel 2009). Of note, activation of SIRT1 precedes that of AMPK, suggesting that leucine activation of SIRT1, rather than AMPK, is the primary event (Liang et al. 2014). Additionally, using an animal model (high-fat die-fed male C57BL/6J mice), leucine supplementation correlates with increased expression of SIRT1 and decreased acetylation (activation) of PGC-1α, contributing to up-regulation of genes controlling mitochondrial biogenesis and fatty acid oxidation (Li et al. 2012). Of great importance, AMPK is required for SIRT1’s ability to promote mitochondrial biogenesis and fatty acid oxidation by leucine. Thus, addition of leucine within physiological ranges improves mitochondrial function. However, chronic exposure to elevated concentrations of leucine (≥1.0 mM) reduces the synthesis of nitric oxide from l-arginine by endothelial cells (Yang et al. 2015) and should be avoided. This illustrates the need to consider amino acid balance in diets when nutritional strategies are used to improve muscle mass and function (Hou et al. 2015b; Wu et al. 2014).
The effects of BCAA, particularly leucine, on muscle mitochondrial biogenesis and fatty acid oxidation are actually regulated by the metabolite of HMB (Stancliffe 2012). HMB, a metabolite of leucine, is produced in tissues of animals and humans (Nissen and Abumrad 1997). HMB, which is commercially available, has been claimed to build skeletal muscle and strength in both exercise and clinical settings, while increasing fatty acid oxidation, a marker of mitochondrial function (Cheng et al. 1997, 1998; Slater and Jenkins 2000; Wilson et al. 2008). HMB (0.5 μM) combined with metformin and resveratrol markedly increases fat oxidation, SIRT1 activity, and AMPK in muscle cells (Bruckbauer and Zemel 2013). Additionally, HMB also stimulates the expression of mitochondrial regulatory (PGC-1α and NRF-1) and component (UCP3) genes in murine myotubes, and increases mitochondrial biogenesis by 50 % in C2C12 myotubes (Stancliffe 2012). Moreover, HMB may play a role in the production of coenzyme Q, a downstream metabolite of 3-hydroxy-3-methylglutarylcoenzyme A, which plays a crucial role in myocyte proliferation and mitochondrial function (Evans and Rees 2002). As such, HMB may be able to improve muscle health by promoting mitochondrial biogenesis (Fig. 3). However, in vivo effects of HMB on skeletal muscle mitochondrial biogenesis in animals and humans are not known.
Clinical effects of HMB supplementation on skeletal muscle health
Exercise induces changes in skeletal muscle by transforming the myofibers from glycolytic to oxidative forms, rendering them more resistant to fatigue and atrophy. Conversely, aging is associated with skeletal muscle atrophy, which is characterized by a progressive loss of oxidative fibers (Aspnes et al. 1997; Chalkiadaki et al. 2014). In recent years, HMB has been an interesting target for studies because of its efficacy as a potent therapeutical supplement for the treatment of muscle disorders (Smith et al. 2004, 2005; Eley et al. 2007, 2008a, b).
The first studies investigating the effect of oral supplementation with different doses of HMB on the mediation of muscle mass in humans were performed in a resistance training study in 1996 (Nissen et al. 1996). The authors reported that dietary supplementation with 0, 1.5, and 3.0 g/day of HMB to humans undergoing resistance training for 3 weeks resulted in a decrease in exercise-associated muscle proteolysis during the first 2 weeks and a reduction in muscle damage during the third week. When subjects were supplemented with 3.0 g/day of HMB, while doing resistance training for 7 weeks, they exhibited a marked increase in fat-free mass and strength (Jowko et al. 2001). Likewise, when 39 men and 36 women between 20- and 40-year old were randomized to either HMB supplementation (3.0 g/days) or placebo in two gender cohorts, HMB increased upper body strength and minimized muscle damage when combined with a 4-week exercise program (Panton et al. 2000). Furthermore, HMB coupled with exercise has been widely used by athletes in an effort to enhance their strength and muscle mass (Nissen and Sharp 2003). In line with these observations, dietary supplementation of HMB was effective in decreasing muscle proteolysis observed in mice implanted with the MAC16 tumor, which is reflected in the attenuation of muscle mass loss (Smith et al. 2005). There is also evidence that HMB might attenuate the muscle loss caused by aging (Vukovich et al. 2001), cancer cachexia (Zanchi et al. 2011), AIDS (Clark et al. 2000), and endotoxemia (Russell and Tisdale 2009; Kovarik et al. 2010). In addition, recent studies have demonstrated that dietary HMB supplementation attenuates dexamethasone-induced muscle wasting and might be used to prevent steroid myopathy (Noh et al. 2014). It is unknown whether HMB has a direct or indirect effect on the observed positive change in skeletal muscle mass.
Studies addressing the efficacy of the combination of supplementation of HMB with other nutrients, resulting in potentially increased strength and lean mass, are also of great importance. In this context, volunteers received dietary supplementation with HMB, creatine, a combination of both, or a placebo, and underwent strength training for 3 weeks. The authors found a higher gain in skeletal muscle strength and mass in the group supplemented with HMB and creatine, compared to the other groups, and a reduction in muscle damage and protein degradation in the group supplemented with HMB (Jowko et al. 2001).
Taken together, HMB has been evaluated alone or in combination with other nutrients, with or without exercise, as a supplement to augment LBM and to treat exercise, sepsis, and cancer-induced muscle damage. However, it is unclear whether these effects of HMB have negative effects on non-muscle tissues (such as liver and white adipose tissue). Bearing this question in mind, researchers carried out studies to evaluate the effects of HMB supplementation on skeletal muscle hypertrophy and the expression of proteins involved in insulin signaling. In this study, rats were treated with saline or HMB (320 mg/kg body weight) for 1 month (Pimentel et al. 2011). The authors found that HMB supplementation stimulated muscle hypertrophy in extensor digitorum longus (EDL) and soleus muscles, while enhancing serum insulin levels, the expression of the mammalian target of rapamycin, and phosphorylation of the 70 kDa ribosomal protein S6 kinase 1 in EDL muscle (Pimentel et al. 2011). Expression of the insulin receptor was enhanced only in liver. These observations indicate that HMB supplementation can be used to increase muscle mass without adverse health effects (Pimentel et al. 2011). Overall, HMB supplementation is safe and may potentially improve several markers of health. Additionally, the usual dose of 3 g/day may be routinely recommended to maintain or improve skeletal muscle mass and function in health and disease (Molfino et al. 2013).
Summary and perspectives
Our fundamental knowledge of the HMB regulation of skeletal muscle mitochondrial biogenesis and health has been greatly expanded over the past 20 years. Understanding the important role for HMB in mitochondrial biogenesis and muscle health may provide new strategies to improve human health and meat quality in livestock production. Importantly, HMB can be used as a nitrogen-free supplement to benefit the environment by reducing nitrogen excretion. Further studies are warranted to clearly define the effects of dietary HMB supplementation on in vivo skeletal muscle mitochondrial biogenesis in healthy subjects and farm animals.
Abbreviations
- AMPK:
-
AMP-activated protein kinase
- BCAA:
-
Branched-chain amino acid(s)
- BCAAem:
-
Branched-chain amino acid-enriched mixture
- CaMK:
-
Calmodulin-dependent protein kinase
- CaMKKβ:
-
Ca2+-activated kinase calmodulin-dependent kinase kinase-β
- EDL:
-
Extensor digitorum longus
- ERRα:
-
Estrogen-related receptor α
- HMB:
-
β-Hydroxy-β-methylbutyrate
- LBM:
-
Lean body mass
- LKB1:
-
Liver kinase B1
- Mef2:
-
Myocyte enhancer factor 2
- MHC:
-
Myosin heavy chain
- OXPHOS:
-
Oxidative phosphorylation
- PGC-1α:
-
Peroxisome proliferator-activated receptor gamma co-activator 1-alpha
- PPARα:
-
Peroxisome proliferator-activated receptor α
- ROS:
-
Reactive oxygen species
- SIRT1:
-
Silent information regulator transcript 1
- TFAM:
-
Mitochondrial transcription factor A
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Acknowledgments
This study was jointly supported by the National Natural Science Foundation of China (31330075;31110103909, 31572416, and 31372319), Special Fund for Agro-scientific Research in the Public Interest (201403047), Innovation Research Team Development Program of MOE of China (IRT0945), The Chinese Academy of Science STS Project (KFJ-EW-STS-063), Key Projects in the National Science and Technology Pillar Program (2013BAD21B04), Hunan Key Project (2015NK1002), Changsha Lvye Biotechnology Limited Company Academician Expert Workstation, Guangdong Wangda Group Academician Workstation for Clean Feed Technology Research and Development in Swine, Guangdong Hinapharm Group Academician Workstation for Biological Feed and Feed Additives and Animal Intestinal Health, Hunan New Wellful Co. Ltd, Academician Workstation, Hubei Provincial Key Project for Scientific and Technical Innovation (2014ABA022), Hubei Hundred Talent program, and the Natural Science Foundation of Hubei Province (2013CFA097, 2013CFB325, 2012FFB04805, and 2011CDA131).
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X. He and Y. Duan contributed equally to this study.
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He, X., Duan, Y., Yao, K. et al. β-Hydroxy-β-methylbutyrate, mitochondrial biogenesis, and skeletal muscle health. Amino Acids 48, 653–664 (2016). https://doi.org/10.1007/s00726-015-2126-7
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DOI: https://doi.org/10.1007/s00726-015-2126-7