A metabolic link to skeletal muscle wasting and regeneration

Abstract

Due to its essential role in movement, insulating the internal organs, generating heat to maintain core body temperature, and acting as a major energy storage depot, any impairment to skeletal muscle structure and function may lead to an increase in both morbidity and mortality. In the context of skeletal muscle, altered metabolism is directly associated with numerous pathologies and disorders, including diabetes, and obesity, while many skeletal muscle pathologies have secondary changes in metabolism, including cancer cachexia, sarcopenia and the muscular dystrophies. Furthermore, the importance of cellular metabolism in the regulation of skeletal muscle stem cells is beginning to receive significant attention. Thus, it is clear that skeletal muscle metabolism is intricately linked to the regulation of skeletal muscle mass and regeneration. The aim of this review is to discuss some of the recent findings linking a change in metabolism to changes in skeletal muscle mass, as well as describing some of the recent studies in developmental, cancer and stem-cell biology that have identified a role for cellular metabolism in the regulation of stem cell function, a process termed "metabolic reprogramming."

Keywords: cell fate; glycolysis; metabolism; satellite cells; stem cells.

Figure 1

Schematic of the process of fatty-acid oxidation (FAO) in cells. Fatty-acid-CoA (FA-CoA) is converted to an acyl carnitine derivative in the mitochondrial membrane, acylcarnitine is then converted back to FA-CoA within the mitochondria where it undergoes a series of dehydrogenation reactions to form acetyl-CoA. Acetyl-CoA, in turn enters the tricarboxylic acid (TCA) cycle to generate NADH to drive complex I, and succinate to drive complex II of the mitochondrial electron transport chain.

Figure 2

Considered one of the master regulators of protein synthesis, mammalian target of rapamycin (mTOR) is perfectly positioned to receive feedback regarding the cellular energy status. During levels of high glycolytic flux, the ADP/ATP ratio is low, and so AMPK activity is reduced, furthermore, GAPDH is prevented from interacting with the small GTPaseRheb. Together, these pathways lead to elevated mTOR complex I (mTORCI) signaling, and protein synthesis.

Figure 3

Highly proliferative cell populations, such as some tumors, ESCs, iPSCs, and SCs require a ready supply of carbon and nitrogen for the generation of new biomass (nucleotides, proteins, phospholipids). To achieve this, many highly proliferative cell populations switch to a predominantly glycolytic based metabolism, but upregulate the PKM2 splice isoform of pyruvate kinase. In this manner, proliferating cells can build up sufficient glycolytic intermediates for the biomass necessary for cell division.