Molecular and biochemical regulation of skeletal muscle metabolism

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Abstract

Skeletal muscle hypertrophy is a culmination of catabolic and anabolic processes that are interwoven into major metabolic pathways, and as such modulation of skeletal muscle metabolism may have implications on animal growth efficiency. Muscle is composed of a heterogeneous population of muscle fibers that can be classified by metabolism (oxidative or glycolytic) and contractile speed (slow or fast). Although slow fibers (type I) rely heavily on oxidative metabolism, presumably to fuel long or continuous bouts of work, fast fibers (type IIa, IIx, and IIb) vary in their metabolic capability and can range from having a high oxidative capacity to a high glycolytic capacity. The plasticity of muscle permits continuous adaptations to changing intrinsic and extrinsic stimuli that can shift the classification of muscle fibers, which has implications on fiber size, nutrient utilization, and protein turnover rate. The purpose of this paper is to summarize the major metabolic pathways in skeletal muscle and the associated regulatory pathways.

This review summarizes the major metabolic pathways in skeletal muscle and the associated regulatory pathways.

Introduction

Beyond its fundamental function of locomotion and thermogenesis, skeletal muscle plays an essential role in whole body metabolic equilibrium. In healthy individuals, skeletal muscle represents about 40% of body mass, is a significant contributor to basal energy expenditure (Zurlo et al., 1990), and accounts for 70%–90% of insulin-mediated glucose disposal (DeFronzo et al., 1981; Shulman et al., 1990). As a result, modulation of skeletal muscle metabolism and insulin sensitivity has proven to be an effective means of alleviating metabolic disorders in humans (Izumiya et al., 2008; Meng et al., 2013; Song et al., 2013). Skeletal muscles are composed of a heterogeneous population of muscle cells with distinct metabolic characteristics (Holloszy, 1967) and demonstrate enormous plasticity to adapt to changing external stimuli including activity, load, nutritional factors, and external conditions. For example, endurance exercise or resistance training increases metabolic demand and subsequently increases skeletal muscle mitochondrial content and oxidative capacity (Donges et al., 2012; Di Donato et al., 2014). Contrarily, conditions associated with the onset of obesity such as excessive calorie intake, in combination with a reduction in workload, decrease oxidative capacity (Mootha et al., 2003), which is associated with metabolic syndrome and poor insulin sensitivity (Simoneau et al., 1995). However, diabetic and obese patients subjected to exercise training regimes have improved insulin sensitivity, albeit significantly blunted compared to healthy individuals (Rosholt et al., 1994; Han et al., 1997; Fueger et al., 2004). Overall, greater muscle oxidative capacity can provide protection against metabolic disorders, attenuate age-related muscle atrophy, and alleviate metabolic defects associated with some myopathies (Conley et al., 2000; Wang et al., 2004; Wenz et al., 2008; Wenz et al., 2009; Ljubicic et al., 2011). Although skeletal muscle metabolism has become the center of attention in the fight against metabolic disorders in humans, modulation of skeletal muscle metabolism in meat-producing animals as a means to improve production efficiency remains largely unexplored.

Although it is apparent that glycolytic metabolism in skeletal muscle is associated with more efficient lean growth, the regulatory mechanisms that drive metabolic changes are undefined. For example, a greater propensity for glycolytic metabolism is associated with high feed efficiency (FE) in pigs, whereas low FE pigs exhibit an increase in oxidative enzyme expression (Le Naou et al., 2012; Fu et al., 2017). Furthermore, ractopamine, a pharmacological agent that promotes lean accretion and improves FE (Williams et al., 1994; Main et al., 2009; Hinson et al., 2011), induces a shift in muscle fiber composition to increase glycolytic capacity (Depreux et al., 2002; Gunawan et al., 2007; Gunawan et al., 2020). However, the adaptive mechanism that facilitates these changes remains elusive. Herein, we review the basics of skeletal muscle metabolism and then delve into our current understanding of skeletal muscle metabolic regulation.

The biochemistry of skeletal muscle metabolism

Skeletal muscle has the remarkable ability to adjust its energy expenditure according to energy demands. Within milliseconds, muscle can increase its energy expenditure 100-fold to transition between resting and active states (Sahlin et al., 1998). Despite these large fluctuations in energy demands, adenosine triphosphate (ATP) concentrations remain relatively constant (Arnold et al., 1984; Heineman and Balaban, 1990), which depicts the striking precision of cellular energy production systems to equal demand. This metabolic control is governed by intricate signaling and feedback loops that relay cellular energy status to alter metabolic pathways within the cell.

ATP homeostasis

Skeletal muscle metabolism is a series of complex biochemical processes that convert nutrients into chemical energy in the form of adenosine triphosphate (ATP; Figure 1 ). There are several metabolic pathways found in muscle cells that have different subcellular locations and substrate utilization with varying longevity. For brief, rapid mobilization of ATP, the phosphagen system is a reversible reaction that catalyzes the degradation of phosphocreatine (PCr) by creatine kinase to produce creatine (Cr) and brief supplies of ATP from adenosine diphosphate (ADP) (PCr + ADP ↔ Cr + ATP). Additionally, the enzyme adenylate kinase collaborates with the phosphagen system to contribute to short-term energy buffering to produce 1 ATP and 1 adenosine monophosphate (AMP) from 2 ADP (2 ADP ↔ 1 ATP + 1 AMP). Adenylate kinase is also an important contributor to reporting cellular energy status by translating relatively small changes in the ATP:ADP ratio into large changes in AMP concentrations. The concentration of cellular AMP is a sensitive indicator of cellular energy status, and small increases are potent allosteric activators of several metabolic enzymes to increase ATP production. For example, 5ʹ-adenosine monophosphate-activated protein kinase (AMPK) increases glycogenolysis by activating glycogen phosphorylase and increases glucose uptake through greater glucose transporter type 4 (GLUT4) expression (Zheng et al., 2001) and translocation (Kurth-Kraczek et al., 1999). In fact, chronic activation of AMPK alters skeletal muscle metabolic characteristics. Furthermore, AMPK activation increases glucose conversation to glucose-6-phosphate through hexokinase activation (Stoppani et al., 2002), the first step of glycolysis. These temporary energy buffering systems maintain ATP levels until other energy production systems are fully active.

Major metabolic pathways in skeletal muscle. Glucose or glycogen can be metabolized through glycolysis to yield pyruvate, which can be converted to acetyl-CoA by PDH or converted to lactate by LDH. Alternatively, the glycolytic intermediates G6P or F6P can be redirected to the PPP, for biosynthetic processes, or to the HBP, for metabolic signaling. If pyruvate is converted to acetyl-CoA, it can feed into the TCA cycle to be fully oxidized, to produce the reducing equivalents NADH and FADH₂, or exit the cycle to contribute to biosynthetic processes, such as fatty acid or amino acid synthesis. Created with BioRender.com.

Glycolysis

Glycolysis converts glucose into pyruvate through a series of enzymatic reactions and can produce ATP 100 times faster than oxidative phosphorylation (OxPhos) (Pfeiffer et al., 2001). Large glycogen stores in muscle allow for rapid mobilization of glucose-1-phosphate by glycogen phosphorylase to fuel glycolysis, which is the predominate energy source during high-intensity exercise (Katz et al., 1986). Alternatively, GLUT4 permits plasma glucose uptake, although rate of uptake is limited by the transport of GLUT4 to the cell surface (Zisman et al., 2000). Translocation of GLUT4 vesicles can be stimulated by insulin in response to high blood glucose levels after feeding; however, its translocation is impaired with insulin resistance and/or diabetes (Zorzano et al., 1996; Zierath et al., 1998; Tremblay et al., 2001). Alternatively, contractile activity from acute exercise can stimulate GLUT4 translocation in an insulin-independent manner (Hayashi et al., 1997; Kennedy et al., 1999; Jessen and Goodyear, 2005). Once within the cells, glucose is rapidly phosphorylated by hexokinase to produce glucose-6-phosphate (G6P) to prevent its outward diffusion and maintain the concentration gradient for continued glucose influx. In either case of glycogen breakdown or glucose uptake, G6P can then branch into anabolic (pentose phosphate pathway), metabolic signaling (hexosamine biosynthetic pathway), or catabolic (glycolysis) pathways depending on cellular demands.

Pentose phosphate pathway

The pentose phosphate pathway (PPP) emanates from the glycolytic intermediates G6P and fructose-6-phosphate (F6P) for synthesis of metabolites that are necessary for skeletal muscle anabolism including ribulose-5-phosphate for nucleic acid synthesis, erythrose-4-phosphate for aromatic amino acid synthesis, and nicotinamide adenine dinucleotide phosphate (NADPH) for reductive biosynthesis reactions such as lipogenesis. The two enzymes glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) are often used to assess PPP activity because they catalyze the first committed step in the PPP and the final step that produces ribulose 5-phosphate, respectively. Activity of the PPP is quite low in skeletal muscle compared to other tissue types (Battistuzzi et al., 1985), which is not surprising considering skeletal muscle is a terminally differentiated tissue. However, in regenerating muscle, 24 h after damage, G6PDH and 6PGDH activities increase 9-fold compared to the undamaged controls (Wagner et al., 1978). Furthermore, skeletal muscle-specific overexpression of AKT serine/threonine kinase 1 (AKT1) induces muscle hypertrophy (Izumiya et al., 2008), accompanied by a 3.5- and 2.3-fold increase in G6PDH and 6PGDH transcripts, respectively (Wu et al., 2017). These results collectively suggest greater PPP flux augments skeletal muscle growth.

Hexosamine biosynthetic pathway

The hexosamine biosynthetic pathway (HBP) is a metabolic signaling pathway that diverts about 2%–3% of cellular glucose from glycolysis (Marshall et al., 1991). It originates from the glycolytic intermediate F6P and is catalyzed by the rate-limiting enzyme glutamine: fructose 6-phosphate amidotransferase (GFAT), which converts F6P and glutamine to glucosamine-6-phosphate and glutamate. The subsequent steps of the HBP generate uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). Collectively, UDP-GlcNAc is indicative of the cellular nutrient flux by integrating carbohydrate, lipid, nucleotide, and protein metabolism (Slawson et al., 2010; Hanover et al., 2012; Ruan et al., 2013). As such, the level of UDP-GlcNAc is an indicator of cellular nutrient status, as it reflects the conditions of nutrient excess or scarcity. Ultimately, UDP-GlcNAc is a donor substrate for the post-translational modification, O-linked-N-acetylglucosaminylation (O-GlcNAcylation), which modifies cell behavior according to fluctuating nutrient conditions (Harwood and Hanover, 2014).

The TCA cycle and oxidative phosphorylation

On the other hand, once F6P is converted to fructose-1,6-bisphosphate by phosphofructokinase (PFK), it is committed to glycolysis and then undergoes a sequential, multi-step conversion to pyruvate. Pyruvate can then be converted to either lactate by lactate dehydrogenase (LDH) or acetyl CoA by pyruvate dehydrogenase (PDH). During periods of rapid glycolytic flux, or in anaerobic conditions, pyruvate is converted to lactate which can then be shuttled out of the cell through monocarboxylase transporters (MCT) to the liver for hepatic gluconeogenesis to replenish glycogen stores (Brooks, 1986). Alternatively, pyruvate can be transported into the mitochondrial matrix for oxidation but must first traverse the outer mitochondrial membrane, presumably through the porin channel (Huizing et al., 1996), and the inner mitochondrial membrane, through the mitochondrial pyruvate carrier (Bricker et al., 2012; Herzig et al., 2012). Once inside the matrix, PDH converts pyruvate into acetyl-CoA to enter into the tricarboxylic acid (TCA) cycle, or less frequently, pyruvate carboxylase converts pyruvate into oxaloacetate to support anaplerosis. As PDH is the major link between glycolysis and the TCA cycle, it is an important molecular switch that controls the transition between the two metabolic pathways and is tightly regulated via phosphorylation. A balance between pyruvate dehydrogenase kinases (PDK) and pyruvate dehydrogenase phosphatases (PDP) regulates the pyruvate dehydrogenase complex (PDC) in response to nutritional status. Pyruvate dehydrogenase kinase 4 (PDK4) is largely found in skeletal muscle (Bowker-Kinley et al., 1998) and has an increased activity during periods of starvation or high fat feeding (Wu et al., 1998; Holness et al., 2000; Jeoung et al., 2006; Jeoung and Harris, 2008), which suggests that PDK4 plays an important role in dietary regulation of carbohydrate oxidation.

Fatty acids also fuel the TCA cycle through β-oxidation, which breaks down fatty acid chains by cleaving two carbons per cycle to produce acetyl-CoA. The four main enzymes involved in the β-oxidation cycle are acyl-CoA dehydrogenase, enoyl-CoA hydratase, hydroxyacyl-CoA dehydrogenase, and ketoacyl-CoA thiolase. One cycle produces acetyl-CoA, a fatty acid chain that is two carbons shorter, nicotinamide adenine dinucleotide (NADH), and flavin adenine dinucleotide (FADH₂). Acetyl-CoA then proceeds into the TCA cycle and the reducing equivalents are oxidized in the electron transport chain (ETC) to produce ATP. Products of these reactions are allosteric regulators of β-oxidation enzymes including their intermediate product, the ratio of NADH/NAD+, and acetyl-CoA levels (Eaton, 2002). Peroxisome proliferator-activated receptors (PPARs) and coactivator peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α) are the major transcriptional regulators of β-oxidation. In fact, deletion of PPARβ in skeletal muscle results in a metabolic shift that decreases muscle oxidative capacity (Schuler et al., 2006) and ablation of skeletal muscle PGC1α increases the number of glycolytic fibers (Handschin et al., 2007), which may have implications on feed efficiency. Indeed, pigs with improved measurements of feed efficiency downregulate mitochondrial energy metabolic enzymes (Jing et al., 2015; Fu et al., 2017).

Acetyl-CoA can be fully oxidized in the TCA cycle to produce the reducing equivalents NADH and FADH₂ for ATP synthesis, or its intermediates can exit the cycle through biosynthetic processes. Although the TCA cycle is often referred to as a “cycle,” implying a unidirectional and defined series of reactions, there are many entry and exit points that allow for both catabolic and anabolic processes in response to different cellular demands. During anabolic conditions, TCA intermediates can be shuttled from the mitochondrial matrix into the cytosol for fatty acid, amino acid, and nucleotide synthesis (Ahn and Metallo, 2015). On the other hand, high energy demand elicits catabolic processes, and intermediates undergo multiple oxidation steps to supply the electron transport chain (ETC) with reducing equivalents (NADH and FADH₂) to replenish ATP stores through OxPhos.

Not surprisingly, the TCA cycle is tightly coupled to energy demand through complex feedback loops. For example, accumulation of NADH is a potent inhibitor of all TCA cycle regulatory enzymes, and as such, malfunctions in the ETC have implications on the TCA cycle (Martinez-Reyes and Chandel, 2020). Similarly, high ATP concentrations or accumulation of TCA cycle intermediates inhibit several TCA enzymes. On the other hand, high energy demands increase AMP levels, which is an allosteric activator of the regulatory TCA cycle enzymes. Although allosteric regulation provides dynamic feedback to keep the TCA cycle in-check, it is also governed by other signaling pathways that provide another layer of regulation. In skeletal muscle, mitochondria are largely found anchored to the sarcoplasmic reticulum (SR) (Boncompagni et al., 2009), which allows for bidirectional signaling between the two organellar systems. More specifically, the calcium released from the SR during muscle contraction can be sequestered by mitochondria, which subsequently stimulates the TCA cycle and mitochondrial ATP production by activating pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, isocitrate dehydrogenase, and the F₁F₀-ATPase (McCormack and Denton, 1979; McCormack et al., 1990; McCormack and Denton, 1993; Hansford, 1994). The parallel activation of muscle contraction and mitochondrial metabolism simultaneously initiates muscle contraction and ATP production to match energy demand with energy supply effectively (Korzeniewski, 2007). In summary, skeletal muscle metabolism is tightly regulated through a series of complex biochemical processes orchestrated by a hierarchy of catabolic and anabolic events.

Mitochondria bioenergetics and dynamics

Multifaceted functions of mitochondria

Although mitochondria are well-known for ATP production, they also play a central role in metabolic signaling (Hansford and Zorov, 1998; Bohovych and Khalimonchuk, 2016; Martinez-Reyes and Chandel, 2020), reactive oxygen species (ROS) production/signaling and scavenging (Skulachev, 1996; Aon et al., 2010; Brand, 2010), cell death (Goldstein et al., 2000), ion and metabolite transport (Palmieri and Pierri, 2010), iron-sulfur protein biogenesis (Nuth et al., 2002; Bulteau et al., 2004; Yoon and Cowan, 2004), and calcium homeostasis (Deluca and Engstrom, 1961; Vasington and Murphy, 1962; Rottenberg and Scarpa, 1974). Mitochondria have two membranes, the porous outer mitochondrial membrane (OMM) and selective inner mitochondrial membrane (IMM), which give rise to the inner membrane space (IMS) and mitochondrial matrix. Residing in the IMM, electron transport chain complexes transfer electrons from reducing equivalents to electron acceptors through several redox reactions that are coupled with the transfer of protons from the matrix to the IMS, generating an electrochemical gradient ( Figures 1 and ​ and2). 2 ). The mitochondrial membrane potential, or electrochemical gradient, is harnessed for ATP production but is also the driving force for its other central metabolic roles.

The electron transport chain and generation of the electrochemical gradient. The ETC consists of four protein complexes (CI-CIV) and two electron transfer carriers, ubiquinone and cytochrome c. The electron donors, NADH and FADH₂, are oxidized by CI or CII, respectively, to reduce the first electron carrier ubiquinone to ubiquinol. Although both CI and CII transport electrons, CI also pumps four protons into the IMS, whereas CII does not pump protons. CIII catalyzes the transfer of electrons from the first electron carrier to the second (ubiquinol to cytochrome c) and pumps four protons into the IMS. Complex IV catalyzes the transfer of electrons from cytochrome c to the terminal electron carrier oxygen to produce water and pumps protons. Complexes are arranged into super complexes in the cristae, often into arrangements of I + III₂ + IV, III₂ + IV, and dimers of ATP synthase (CV). In normal physiological conditions, proton re-entry into the matrix largely occurs through the ATP synthase (CV), coupling the electrochemical gradient to ATP production. However, there are alternative re-entry points that are uncoupled from ATP production, such as uncoupling proteins (UCPs) to produce heat and the nicotinamide nucleotide transhydrogenase (NNT) to replenish NAPDH pools for biosynthetic processes and ROS scavenging. Created with BioRender.com.

Mitochondria in different subcellular locations also have variable roles in skeletal muscle physiology. Intrafibrillar mitochondria (IFM) are positioned between myofibrils that wrap around the I-band of the sarcomere (Bleck et al., 2018) and form extensive networks that facilitate rapid distribution of ATP to myofibrillar ATPases to support muscle contraction (Willingham et al., 2021). Peripherally located mitochondria (PM) localize to capillaries (paravascular mitochondria; PVM) or nuclei (paranuclear; PNM) (Glancy et al., 2014; Glancy et al., 2015) and are less branched and larger than IMF (Picard et al., 2013), which increases matrix and cristae volume. However, the bioenergetic differences between PVM and PNM remain unclear.

Electron transport chain

Four transmembrane protein complexes and two electron carriers are the basis for generating the mitochondrial membrane potential ( Figure 2 ). Through a series of redox reactions, electrons are transported from complex to complex while pumping protons from the matrix to the IMS. Complex I (CI) and complex II (CII) oxidize the electron carriers NADH or FADH₂, respectively, to reduce the electron carrier ubiquinol. In the process, CI pumps protons across the IMM, whereas CII does not. Complex III (CIII) and complex IV (CIV) then catalyze the electron transfer from ubiquinol to cytochrome c and from cytochrome c to oxygen, respectively, to produce water and pump protons. Protons in the IMS can then re-enter the matrix through the F₁F₀ ATPase, also known as complex V (CV), where the energy generated from protons flowing down a concentration gradient is harnessed to phosphorylate ADP to produce ATP, termed OxPhos. The majority of proton re-entry is coupled to ATP production; however, alternative routes of re-entry exist that bypass CV, such as uncoupling proteins to produce heat or the nicotinamide nucleotide transhydrogenase to replenish the NADPH pool for biosynthetic processes ( Figure 2 ).

Although ETC complexes are routinely simplified as linear complexes in numerical order with a 1:1 ratio of complexes, their stoichiometry varies considerably (Schagger and Pfeiffer, 2001). Within the IMM folds, or cristae, complexes can be found as freely floating or in super-assembled structures known as supercomplexes. In mammalian cells, supercomplexes are largely composed of a combination of CI, CIII, and CIV, whereas the contribution of CII and CV to the formation of supercomplexes remains poorly understood (Acin-Perez et al., 2008). Their formation, although not fully understood, have been suggested to play a role in complex stability (Acin-Perez et al., 2004; Diaz et al., 2006), electron transport efficiency (Bianchi et al., 2004), and control of ROS production (Ghelli et al., 2013; Maranzana et al., 2013). Interestingly, supercomplex formation increases with exercise (Greggio et al., 2017), indicating that supercomplexes may be an adaptive mechanism to meet increased energy demands.

Mitochondrial dynamics

In skeletal muscle, mitochondria morphology and functions are quite responsive to a range of intermittent and continuous stimuli including exercise (Menshikova et al., 2006), nutritional factors (Mishra et al., 2015), aging (Coggan et al., 1992; Cooper et al., 1992; Short et al., 2005), and disease (Simoneau et al., 1995; Mootha et al., 2003; Patti et al., 2003). Mitochondrial adaptations include the ability to alter their abundance, ETC activity (oxidative capacity), coupling, and structure. Of those, the most rapid and fluid response is the change of structure (Eisner et al., 2014), which allows for dynamic mitochondrial remodeling to adapt to the cellular environment (Glancy et al., 2015). Mitochondrial dynamics are a coalition of fusion and fission events that are important for mitochondrial biogenesis, stress mitigation, and quality control by enabling the removal of damaged mitochondria (mitophagy; Figure 3 ). Fusion is mediated by mitofusion proteins (Mfn1 and Mfn2) and optic atrophy protein 1 (Opa1) to fuse the inner and outer mitochondrial membranes, respectively (Koshiba et al., 2004; Meeusen et al., 2004; Meeusen et al., 2006; Song et al., 2009). Deletion of Mfn1 and Mfn2 in skeletal muscle decreases oxidative capacity, reduces mitochondrial DNA (mtDNA) abundance, reduces muscle mass, and eventually leads to lethality (Chen et al., 2010a). On the other hand, fission events require the translocation of dynamin-related protein 1 (Drp1) from the cytosol to wrap around the outer membrane and cleave it (Ji et al., 2015; Kalia et al., 2018; Fonseca et al., 2019). Although there are other proteins involved in fission, loss of Drp1 inhibits fission and results in hyperfusion of mitochondria (Fonseca et al., 2019). Skeletal muscle specific ablation of Drp1 results in muscle atrophy, distorted mitochondrial morphology, and impaired mitochondrial respiration (Favaro et al., 2019). Although a physiological decrease in Drp1 may facilitate hypertrophy, as overloaded muscle had a decrease in Drp1, increase in fusion proteins, and greater mitochondrial area (Uemichi et al., 2021). Together, the balance of proper mitochondrial fusion and fission is essential for skeletal muscle homeostasis and may play a role in muscle hypertrophy.

An overview of mitochondrial dynamics. Skeletal muscle mitochondria form a dynamic network that is constantly adapting to changing external and internal stimuli. Punctate mitochondria can fuse together to form an interconnected network permitting an increase in oxidative capacity, dispersal of mitochondrial damage to promote survival, or an exchange of mitochondrial content (mtDNA and metabolites). Contrarily, mitochondria can undergo fission to remove damaged mitochondria through mitophagy, facilitate mitochondrial trafficking, or adapt to metabolic changes. Created with BioRender.com.

Mitochondrial dynamics also permit a fluid response to changing nutritional factors. For example, muscle cells isolated from the extensor digitorum longus (EDL) incubated in media containing acetoacetate for 24 h, an oxidative substrate, have more extensive (fused) mitochondrial networks than those treated with glucose for the same amount of time. Fused mitochondrial networks are predominant in oxidative fibers and have high rates of fusion, whereas a greater proportion of punctate mitochondria are found in glycolytic fibers (Mishra et al., 2015). Matrix content is shared in mitochondrial networks, which enables rapid cellular energy distribution (Glancy et al., 2015) and movement of metabolites, ions, proteins, and mtDNA. Thus, extensive mitochondrial networks in oxidative fibers facilitate energy homeostasis, whereas glycolytic fibers have less extensive networks that support short bouts of work through glycolysis. On the other hand, in conditions of nutrient deprivation, mitochondria elongate by downregulating fission events to protect against mitophagy and maximize energy production (Gomes et al., 2011). These findings demonstrate mitochondria readily adapt to support muscle physiology under a wide range of nutrient conditions.

Molecular regulators of skeletal muscle growth and metabolism

Skeletal muscle growth is orchestrated by a hierarchy of complex anabolic and catabolic biological processes that dictate the rate of protein accretion. Skeletal muscle is composed of a heterogenous population of muscle cells (myofibers) that have variable rates of myofibrillar, mitochondrial, and sarcoplasmic protein turnover. As such, protein accretion rate is a function of several myofiber characteristics. Myofibers can be classified according to predominate type of energy metabolism (glycolytic or oxidative metabolism) and speed of contraction (fast or slow). Slow-twitch muscle fibers have a greater rate of protein synthesis than fast-twitch fibers which can be attributed to duration of contraction and mitochondrial abundance, as mitochondrial proteins have higher fractional synthesis rates than myofibrillar proteins (Jaleel et al., 2008). However, slow fibers also have high rates of protein degradation, presumably due to a high mitochondrial content prone to damage from reactive oxygen species, that has a net result of low rates of protein accretion (Lewis et al., 1984) and relatively small fiber size. Therefore, metabolism is a contributing factor to muscle accretion rate and can be exploited to manipulate growth rate and efficiency of substrate utilization. Indeed, skeletal muscle from high-feed efficient pigs have a greater propensity of glycolytic metabolism than low feed efficient pigs (Fu et al., 2017). However, the regulatory mechanisms that facilitate metabolic shifts to promote an improved feed conversion ratio remain elusive.

IGF-Akt signaling

The two major regulatory pathways of protein accretion in muscle are the insulin-like growth factor 1 (IGF-1)/ phosphoinositide-3-kinase-Akt (PI3K-Akt)/ protein kinase B (PKB)/ mammalian target of rapamycin (mTOR) pathway and the myostatin pathway, which are respective positive and negative regulators of protein synthesis. Binding of IGF-1 to its receptor activates PI3K, which phosphorylates phosphoinositide-4,5-biphosphate (PIP2) generating phosphoinositide-3,4,5-triphosphate (PIP3) to act as a docking site for phosphoinositide-dependent kinase 1 (PDPK1) to activate Akt. Activation of Akt inhibits protein degradation through the repression of the forkhead box protein (FOXO) family of transcription factors and stimulates protein synthesis through the activation of mTOR and glycogen synthase kinase 3β (GSK3β). In skeletal muscle, loss of the IGF-1 receptor induces muscle atrophy (Mavalli et al., 2010), whereas IGF-1 overexpression stimulates hypertrophy (Coleman et al., 1995; Musaro et al., 2001; Fiorotto et al., 2003). Similarly, the activation of its downstream target Akt in skeletal muscle induces profound hypertrophy (Lai et al., 2004; Blaauw et al., 2009), whereas deletion of the downstream target mTOR results in impaired postnatal growth and the development of severe myopathy (Risson et al., 2009). Furthermore, loss of mTOR1 diminishes oxidative capacity of soleus and EDL muscles, which suggests that mTOR1 plays a role in modulating metabolic characteristics of skeletal muscle (Bentzinger et al., 2008). As diminished oxidative capacity is often associated with the onset of numerous metabolic diseases and muscle wasting, it is plausible this metabolic shift plays a role in the development of myopathies in muscle lacking mTOR1. Although it is apparent oxidative metabolism is key to longevity and protection against metabolic disease in humans, scientists in animal agriculture have a vastly different objective of facilitating efficient lean accretion rather than alleviating ailments associated with aging. However, these discoveries are still of importance to animal agriculture. For example, overexpression of IGF-1 results in heavier body weights, muscle mass, and a shift to carbohydrates as the primary fuel source (Christoffolete et al., 2015). However, oxygen consumption did not change (Christoffolete et al., 2015), which suggests that IGF-1 mediated hypertrophy is fueled by carbohydrate oxidation. Together, these findings suggest that IGF-1 signaling prioritizes glucose as a fuel source to facilitate hypertrophy, and although it seems that mitochondria play a role, a deeper understanding of this junction is necessary to translate these findings to develop innovative strategies for efficient muscle hypertrophy in meat producing animals.

Myostatin signaling

Myostatin is a negative regulator of muscle growth. Natural mutations of the myostatin gene have been discovered in sheep (Clop et al., 2006), cattle (Grobet et al., 1997; McPherron and Lee, 1997), dogs (Mosher et al., 2007), and humans (Schuelke et al., 2004) that result in gene disruption and a subsequent increase in muscle mass. In mice, myostatin deletion results in a 2-fold increase in muscle mass and decreased adipose tissue deposition (McPherron and Lee, 2002; Hamrick et al., 2006), whereas myostatin overexpression results in a reduction of muscle mass (Reisz-Porszasz et al., 2003). Myostatin deficiency also improves glucose metabolism and decreases mitochondrial respiration (Chen et al., 2010b; Mouisel et al., 2014). Myostatin and IGF-1 have a dynamic interplay that modulates muscle accretion through the two pathways. The PI3K/Akt axis is common to both pathways and permits crosstalk, which is essential for normal muscle growth and physiology. For example, overexpression of myostatin downregulates Akt/mTOR signaling and subsequently decreases protein synthesis (Amirouche et al., 2009). Contrarily, myostatin deletion increases PKB and mTOR activity (Lipina et al., 2010), although presence of the IGF-1 receptor is necessary for efficient hypertrophy (Kalista et al., 2012). Together, both pathways play a role of modulating metabolism and are pertinent in the regulation of muscle hypertrophy.

AMPK signaling

Although proper myostatin and IGF-1 crosstalk are essential for muscle physiology and growth, it is apparent the maintenance of metabolic homeostasis is also crucial. Regulation of skeletal muscle metabolism involves highly integrated signaling pathways that are tightly coupled to nutrient availability and cellular energy status. One example is the dynamic intracellular energy sensor AMPK that regulates muscle metabolism by relaying signals of energetic stress. As ATP is hydrolyzed, AMP levels rise and decrease the ATP:AMP ratio to activate AMPK, which promotes catabolic processes and suppresses anabolic processes to replenish ATP stores. As such, activation of AMPK decreases protein synthesis, an anabolic process, demonstrated by a 45% decrease in skeletal muscle fractional rate of protein synthesis 1 h after injection of the AMPK activating drug 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) (Bolster et al., 2002). AMPK activation decreases protein accretion rates by suppressing mTOR activity and activating FOXO and uncoordinated 51-like kinase 1 (ULK1), regulators of the autophagy pathway (Lee et al., 2010; Kim et al., 2011). Downregulation of anabolic pathways from AMPK activation is also accompanied by greater catabolism to generate ATP and meet the increased energy demand. For example, mutation of the AMPKγ3 subunit in mice (Garcia-Roves et al., 2008) and pigs (Scheffler et al., 2014) results in constitutive activation of AMPK, which increases mitochondrial biogenesis and enhances oxidative capacity of glycolytic muscle. Surprisingly, its chronic activation does not impact muscle growth (Carr et al., 2006), which may be attributed to a compensatory or adaptive mechanism that can override the negative regulation of AMPK on protein synthesis. In fact, Scheffler et al. (2014) found that the AMPKγ3 R200Q mutant pigs had an increase in Akt expression, a positive regulator of muscle growth that may account for the normal growth of these pigs. In agreement, Lantier et al. (2010) reported a skeletal muscle-specific double knockout of AMPKα1 and AMPKα2 increased soleus muscle mass, which further implicates AMPK as a regulator of muscle mass. As a result, the AMPK pathway has become a target to counteract metabolic disorders without negatively impacting muscle mass, as an increase in oxidative capacity enhances the ability of muscle to combat energetic stress providing protection against muscle wasting and metabolic diseases (Conley et al., 2000; Wang et al., 2004; Wenz et al., 2008; Wenz et al., 2009; Ljubicic et al., 2011). Indeed, an increase in oxidative capacity can occur simultaneously with hypertrophy (Scheffler et al., 2014), which suggests that a compensatory pathway exists that can force hypertrophy regardless of metabolic characteristics that has yet to be discovered. In summary, signaling pathways that modulate muscle hypertrophy are complex and intricately interlaced with those that regulate skeletal muscle metabolism, which has downstream implications on lean accretion efficiency.

Nutrient sensing and skeletal muscle adaptation

O-GlcNAcylation

Muscle cells can perceive cellular energy status and substrate availability, and as such, muscle is a plastic tissue that permits metabolic adaptations to environmental changes. During times of nutrient surplus, such as those after feeding, muscle can “sense” the availability of substrates and increase protein accretion. Conversely, periods of nutrient scarcity result in repartition of nutrients away from anabolic processes. The dynamic post-translational modification O-linked-β-D-N-acetylglucosamine (O-GlcNAc) serves as a widespread nutrient gauge by cycling on and off O-GlcNAc moieties to serine and threonine residues of nuclear, cytosolic, and mitochondrial proteins (Hanover et al., 2012). The donor substrate, UDP-GlcNAc, is a product of the HBP and its levels reflect the collective cellular nutrient flux by incorporating nucleotide, carbohydrate, lipid, and protein metabolism. A pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), are responsible for the respective addition and removal of O-GlcNAc from target proteins to modify their function to adapt to cellular nutrient abundance ( Figure 4 ). Collectively, this post-translational modification acts as a nutrient sensing pathway because levels of UDP-GlcNAc, and thus O-GlcNAcylation, are indicative of cellular nutrient status (Walgren et al., 2003; Housley et al., 2008; Kang et al., 2008).

O-GlcNAc signaling pathway. Step 1: the hexosamine biosynthetic pathway incorporates metabolites from protein, carbohydrate, lipid, energy, and nucleotide metabolism to synthesize UDP-GlcNAc, which fluctuates with cellular nutrient status. Step 2: OGT transfers UDP-GlcNAc to any of its thousands of target proteins and OGA removes the O-GlcNAc moiety, known as O-GlcNAcylation, to modulate protein function. O-GlcNAcylation occurs in a similar manner to phosphorylation and may be as widespread, but O-GlcNAcylation patterns correlate to cellular nutrient status and is only mediated through the enzymes OGT and OGA. In skeletal muscle, glycolytic muscle has a greater abundance of O-GlcNAcylated proteins. In fact, several glycolytic enzymes and mitochondrial proteins are targets of OGT, and as such O-GlcNAcylation can modulate skeletal muscle metabolism in response to changing dietary conditions. Created with BioRender.com.

O-GlcNAc transferase

A single gene encodes OGT; however, three isoforms originate from alternative splicing. The two predominant isoforms are nucleocytoplasmic OGT (ncOGT) and mitochondrial OGT (mOGT), which contains an N-terminal mitochondrion targeting sequence. A short isoform of OGT exists, but its functionality remains largely unclear. Until recently, global cellular O-GlcNAcylation has been largely accredited to ncOGT; however, Banerjee et al. (2015) showed that the pyrimidine nucleotide carrier transports UDP-GlcNAc into the matrix and blocking this transporter lowers mitochondrial O-GlcNAcylation, which suggests that robust O-GlcNAc cycling occurs within mitochondria. Sacoman and colleagues (2017) were able to knock down cellular OGT and mOGT in HeLa cells by targeting unique sequences of the splice variants. Knockdown of mOGT altered mitochondrial content, function, and membrane potential; however, knockdown of both mOGT and ncOGT increased mitochondrial content and restored membrane potential. These data suggest that crosstalk between the two isoforms of OGT exists to mediate mitochondrial integrity and function, yet its relation to nutrient status remains elusive.

OGT substrates

Several metabolic enzymes are targets of O-GlcNAcylation. Phosphofructokinase-1, a rate-limiting glycolytic enzyme, is inhibited by O-GlcNAcylation resulting in the redirection of glucose to the PPP in cancer cells (Yi et al., 2012). O-GlcNAcylation of G6PDH, the rate limiting enzyme of the PPP, increases its activity and glucose flux through the PPP in lung cancer cells (Rao et al., 2015). Prolonged exposure of cells to glucose enhances cellular O-GlcNAcylation and subsequently increases glycolytic flux (Marshall et al., 1991; Hanover et al., 1999; Bond and Hanover, 2015). In cardiomyocytes, Hu et al. (2009) reported several subunits of the electron transport chain are O-GlcNAcylated in high glucose conditions, which decrease complex activity and mitochondrial respiration (Hu et al., 2009). Interestingly, removal of O-GlcNAcylation in high glucose conditions restores mitochondrial function to that of cells exposed to normal glucose. These data show that elevated glucose availability signals an increase in O-GlcNAcylation of key regulatory protens to modulate metabolism.

HBP pathway

Glucose and glutamine are both considered rate limiting in the HBP, and as such are potent stimulators of UDP-GlcNAc synthesis and thus O-GlcNAcylation (Walgren et al., 2003; Swamy et al., 2016). Excess free fatty acids also increase UDP-GlcNAc levels in rat skeletal muscle, although the subsequent glucose uptake and handling are markedly different than that stimulated by excess glucose (Hawkins et al., 1997b). In cultured pancreatic beta-cells, high-fat exposure increased UDP-GlcNAc levels and resulted in dysregulated metabolites distinct from those exposed to high glucose (Yousf et al., 2019), which demonstrates that UDP-GlcNAc levels increase in response to different nutrients but their downstream metabolic adaptations vary uniquely.

O-GlcNAcylation and muscle metabolism

O-GlcNAcylation has been well documented in skeletal muscle and has emerged to have an important role in maintaining proper skeletal muscle glucose handling and insulin sensitivity. As skeletal muscle is the largest metabolically active tissue in the body and is responsible for the majority of insulin-mediated glucose disposal, skeletal muscle O-GlcNAcylation is a key player in global metabolism. Early investigation in muscle suggested a correlation between nutrient abundance and insulin resistance in rodents. Indeed, overexpression of GLUT4 in skeletal muscle results in chronic exposure of muscle to glucose, which is accompanied by greater UDP-GlcNAc levels and the development of insulin resistance in mice (Buse et al., 1996). Furthermore, prolonged fatty acid and uridine exposure increase UDP-GlcNAc levels and reduce skeletal muscle insulin sensitivity (Hawkins et al., 1997a; Hawkins et al., 1997b). Contrarily, ablation of OGT, and thus O-GlcNAcylation, in skeletal muscle protects mice from high fat diet induced obesity and insulin resistance (Shi et al., 2018). These findings demonstrate that O-GlcNAcylation in muscle has implications on whole-body metabolism.

Implications of skeletal muscle O-GlcNAcylation in farm animals

In cattle, O-GlcNAcylation is greater in animals on a grain-based diet than those on a forage-based diet (Apaoblaza et al., 2020). As O-GlcNAcylation is an indicator of high nutrient availability, the post-translation modification is presumably a key player in the metabolic shift towards glycolytic metabolism in cattle fed a concentrate diet. Contrarily, forage-based diets that are energy scarce promote oxidative metabolism and have low levels of O-GlcNAcylation. In pigs, low- and high- energy diets also result in distinct patterns of O-GlcNAcylated proteins where high-energy diets have high levels of O-GlcNAcylation (data not published). Collectively, these data document the existence of intact hexamine biosynthesis signaling and O-GlcNAcylation in muscle of meat producing animals and strongly argue that O-GlcNAcylation is part of the complex nutrient sensing machinery that modulates both skeletal muscle and whole body metabolism.

Metabolic and nutritional regulation of satellite cells

Adult skeletal muscle contains a heterogeneous population of stem cells, known as satellite cells (SC), that contribute to postnatal muscle growth, maintenance, and repair (Mauro, 1961; Moss and Leblond, 1971; Kuang et al., 2007; Lepper et al., 2011). Adult SC are predominately in a quiescent state and can activate to support several rounds of proliferation before undergoing self-renewal or terminal differentiation (Schultz et al., 1978; Snow, 1978). Orchestration of these behaviors is tightly synchronized by integrated signaling cascades that relay unfolding intrinsic and extrinsic stimuli.

Metabolic regulation of satellite cells

Intrinsically, metabolism is a strong regulator of SC behavior, during which metabolic shifts occur to accommodate demands of different growth stages ( Figure 5 ). Quiescent SC have a relatively low metabolic rate but can be separated into two distinct metabolic populations. The population with a lower metabolic rate has a delayed cell cycle entry, a slower mitotic rate, and are less transcriptionally primed for myogenic commitment. Contrarily, the population with higher metabolic activity is more responsive to activation (Rocheteau et al., 2012). Once activated, SC begin to proliferate, accompanied by an increase in glycolysis and glutaminolysis to meet energy demands and support macromolecule biosynthesis, which is essential for proliferating cells (Lunt and Vander Heiden, 2011). Within 48 h of differentiation, mitochondrial content and oxidative capacity increase to shift to a more oxidative metabolism (Moyes et al., 1997; Remels et al., 2010). Disruption of this shift through inhibition of mitochondrial protein synthesis (Korohoda et al., 1993; Hamai et al., 1997; Rochard et al., 2000), mitochondrial fission (Bloemberg and Quadrilatero, 2016), mitochondrial DNA replication (Brunk and Yaffe, 1976; Herzberg et al., 1993), or inhibition of OxPhos confines myoblast to a proliferative, single cell state and obstructs myoblast differentiation. Although an oxidative shift is necessary to support differentiation, glucose is still an essential nutrient, which suggests glucose oxidation supports myogenesis. Indeed, obstruction of glucose entry into the TCA cycle through deletion of PDH impairs differentiation (Hori et al., 2019). These findings define the metabolic changes that facilitate myogenesis.

Metabolic changes associated with adult myogenesis. Quiescent SC have minimal metabolic activity and few mitochondria. As SC activate, a rapid increase in metabolic activity takes place that is accompanied by an increase in mitochondrial content, which continues to increase as SC exit the cell cycle to differentiate. In fact, obstruction of mitochondrial biogenesis impedes myogenesis. Images are from isolated and cultured single myofibers that were fixed and incubated in Mitotracker Red (red) and an antibody against Pax7 (green) then counterstained with DAPI (blue) created with BioRender.com.

AMPK signaling

Changes in cellular energy status also have implications on myogenesis. AMPK, activated by changes in AMP:ATP ratios, is a sensor of metabolic stress that signals periods of energy stress to facilitate adaptations to changing internal conditions. Activation of AMPK with the drug AICAR impairs G1/S cell cycle progression and reduces myotube formation (Williamson et al., 2007). On the other hand, deletion of AMPKα1 in SC impairs adult regenerative myogenesis, and SC lacking AMPKα1 transplanted into control muscles have a diminished myogenic capacity (Fu et al., 2016), which suggests that external conditions cannot rescue the loss of AMPKα1 in SC. In addition to impaired regeneration, these cells proliferate more slowly in culture (Fu et al., 2015), which can be attributed to the loss of AMPK obstructing Warburg-like glycolysis. In proliferating cells, an increase in Warburg-like glycolysis is stimulated by AMPK through a decrease in ATP to ADP ratios to support proliferation, whereas non-proliferating cells have a higher ratio of ATP to ADP accompanied by greater mitochondrial function (Maldonado and Lemasters, 2014). Collectively, these findings highlight the importance of AMPK translating cellular energy status to modulate myoblast metabolism for efficient myogenic progression.

Nutrient conditions on satellite cell fate

Extrinsically, conditions of nutrient excess or scarcity are also perceived by SC and alter their behavior accordingly. In SC, O-GlcNAcylation, the widespread nutrient sensing pathway, is essential for normal SC behavior. Loss of OGT, and thus O-GlcNAcylation, impairs SC proliferation and adult regenerative myogenesis (Zumbaugh et al., 2021). More specifically, high circulating levels of amino acids promote SC lineage progression through the mTOR pathway (Dai et al., 2015), a cellular nutrient sensor that regulates protein synthesis rates. For example, supplementation of lysine, the first limiting amino acid in high carbohydrate diets (Li et al., 2012; Zeng et al., 2013), increases mTOR activity, which suppress proteolysis through the autophagic-lysosomal system (Sato et al., 2014) and increases SC proliferation (Jin et al., 2019). Furthermore, leucine supplementation promotes proliferation, differentiation, and skeletal muscle regeneration through the mTORC1 pathway (Pereira et al., 2014; Dai et al., 2015), and leucine restriction inhibitions differentiation (Averous et al., 2012). Indeed, inhibition of mTOR in myoblasts cultured in high leucine concentrations decreases proliferative capacity and protein synthesis (Han et al., 2008). In agreement, conditional deletion of mTOR in adult SC also impairs proliferation, differentiation, and muscle regeneration (Zhang et al., 2015). Collectively, these findings show that the mTOR pathway is essential to translate fluctuations in nutrient abundance to modulate myoblast behavior. In addition to promoting protein synthesis to support myogenesis, mTOR also regulates myogenesis through the expression of several myogenic regulatory factors including Myf5 and MyoD (Averous et al., 2012; Hatfield et al., 2015; Zhang et al., 2015), which play a role in SC activation and transient proliferation (Braun et al., 1992; Rudnicki et al., 1992; Ustanina et al., 2007), and myogenin, which is required for terminal myoblast differentiation (Hasty et al., 1993; Nabeshima et al., 1993). Collectively, these findings demonstrate the importance of adequate nutrient availability and the downstream signaling that indicates cellular nutrient status for proper SC function.

On the other hand, overfeeding or excessive substrate availability negatively impacts SC function (Peterson et al., 2008; D’Souza et al., 2015; Fausnacht et al., 2020). For example, high levels of glucose induce insulin resistance in C2C12 myotubes and inhibit myogenic differentiation (Grzelkowska-Kowalczyk et al., 2013), which is accompanied by a decrease in Akt phosphorylation (Luo et al., 2019). In fact, inhibition of Akt (Luo et al., 2019) or PI3-kinase (Tureckova et al., 2001) recapitulates the high glucose phenotype and inhibits differentiation. As such, activation of the PI3-kinase/Akt pathway is essential for efficient glucose uptake. Indeed, pharmacological activation of Akt in high glucose conditions rescues myogenic differentiation (Luo et al., 2019). These findings demonstrate the PI3-kinase/Akt pathway can “sense” changes in nutrient concentrations to alter SC behavior. Alternatively, short-term calorie restriction improves SC function and increases oxidative metabolism (Cerletti et al., 2012). However, discrepancies in the effectiveness and response to caloric restriction have been debated in regard to sex, age, and duration of restriction (Boldrin et al., 2017; Abreu et al., 2020). In summary, SC are susceptible to changing extrinsic nutrient and intrinsic metabolic conditions through complex signaling pathways that modulate myogenesis.

Summary

Skeletal muscle is a heterogenous population of myofibers and SC with varying metabolic characteristics that influence muscle physiology and myogenesis, respectively. Skeletal muscle metabolism is modulated by several signaling pathways that have implications on fiber size, nutrient utilization, and protein turnover rate. Additionally, myogenesis is governed by distinct metabolic adaptations and signaling pathways that are responsive to changing external conditions. Further investigation into the influence of skeletal muscle and SC metabolic regulation on livestock growth efficiency will provide the framework for an animal scientist to develop selection strategies that may prove useful in augmenting animal growth efficiency and meat production.

Acknowledgments

All figures made using BioRender.com. An acknowledgement for USDA Proposal Number: 2018-07081

Glossary

Abbreviations

Contributor Information

Morgan D Zumbaugh, Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.

Sally E Johnson, Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.

Tim H Shi, Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.

David E Gerrard, Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.

Conflict of Interest Statement

The authors declare no real or perceived conflicts of interest.

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