Specific ATPases drive compartmentalized glycogen utilization in rat skeletal muscle

Abstract

Glycogen is a key energy substrate in excitable tissue, including in skeletal muscle fibers where it also contributes to local energy production. Transmission electron microscopy imaging has revealed the existence of a heterogenic subcellular distribution of three distinct glycogen pools in skeletal muscle, which are thought to reflect the requirements for local energy stores at the subcellular level. Here, we show that the three main energy-consuming ATPases in skeletal muscles (Ca2+, Na+,K+, and myosin ATPases) utilize different local pools of glycogen. These results clearly demonstrate compartmentalized glycogen metabolism and emphasize that spatially distinct pools of glycogen particles act as energy substrate for separated energy requiring processes, suggesting a new model for understanding glycogen metabolism in working muscles, muscle fatigue, and metabolic disorders. These observations suggest that the distinct glycogen pools can regulate the functional state of mammalian muscle cells and have important implications for the understanding of how the balance between ATP utilization and ATP production is regulated at the cellular level in general and in skeletal muscle fibers in particular.

The spatial distribution of glycogen and glycogen consumption in muscle cells

“…These discoveries have led to continuing interest in muscle glycogen and whether glycogen depletion causes fatigue and the possible mechanism(s) involved. The study by Nielsen et al (2022) in this issue adds a further step in this understanding by showing that the three main ATPases in muscle consume glycogen in a spatially distinct manner.…”

“…These sites and the distribution of glycogen granules are shown in Figs. 1 and 2 of Nielsen et al (2022) . Around 29% of the glycogen granules were intramyofibrillar, 65% intermyofibrillar, and 6% subsarcolemmal.…”

“…Glycogen granules are visible in transmission electron microscopy and are recognized to have a distinctive distribution in muscles that depends on species, fiber type, and the history of activity (for review see Ørtenblad et al, 2013 ). In Nielsen et al (2022) , rat soleus muscles were studied and glycogen particles were measured at three different sites using standard stereological techniques. The sites chosen were (1) intramyofibrillar, i.e., within the myofibrils where the granules are concentrated near the Z line; (2) intermyofibrillar, i.e., between the myofibrils, a space that includes SR, transverse tubules (T-tubules), the triads (a diffusion-restricted junctional space where SR and T-tubule membranes come in close contact and SR Ca 2+ release occurs), and mitochondria; and (3) subsarcolemmal, i.e., a relatively narrow space adjacent to the sarcolemma.…”

“…The study by Nielsen et al (2022) represents a further attempt to understand how the spatial consumption of glycogen is affected by various ATPases in muscle. It is generally thought that in working muscles myosin ATPase consumes around 50–60% of ATP, SR Ca 2+ ATPase around 40–50%, and Na + K + ATPase around 5–10%.…”

“… Nielsen et al (2022) studied the third ATPase within muscle, the Na + K + ATPase, in resting muscles by increasing the Na + K + ATPase activity with salbutamol and then blocking it with ouabain. The only ouabain-sensitive pool was the intramyofibrillar glycogen and consumption was reduced by about one half.…”