Molecular and biochemical regulation of skeletal muscle metabolism

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.

Keywords: metabolism; muscle; nutrients; satellite cells.

Figure 1.

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.

Figure 2.

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.

Figure 3.

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.

Figure 4.

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.

Figure 5.

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.