residues are linked linearly with each other viaα(1-4) glycosidic
bonds, and branching chains form every 8–12 residues viaα(1-6)
glycosidic bonds. Glycogen synthase is the enzyme responsible for
attaching UDP-glucose molecules linearly, while branching
enzyme is the one responsible for starting branching chains of
glucosyl residues [2, 3]. The branches and chains of glucose are
attached to a central protein complex called glycogenin.
In humans, glycogen is stored primarily in the liver and muscle
tissues [2]. Normally, glycogen degradation occurs upon acute
metabolic stress situations to sustain energy levels and promote
survival. For instance, starvation and exercise trigger glycogen
degradation in muscle and liver tissues to maintain blood glucose
levels. Upon the need of glucose or glucose-derived metabolites
including glucose-6-phosphate, glycogen is degraded by glycogen
phosphorylase through a phosphorolysis reaction. Both glycogen
synthase and glycogen phosphorylase are regulated by hormonal
cues [2, 3]. When the body needs glucose, epinephrine and gluca-
gon are released to activate glycogen degradation leading to glu-
cose-6-phosphate, an important intermediate that could be used
for different purposes according to the cellular needs [1]. However,
when the body has an excess of glucose that needs to be stored,
insulin is secreted and glucose molecules are stored in the form of
glycogen [3–5]. Glycogen synthase and glycogen phosphorylase
are regulated via phosphorylation and dephosphorylation events
by upstream kinases and phosphatases, respectively. In general,
phosphorylation events activate glycogen phosphorylase and
inhibit the activity of glycogen synthase [4]. Accordingly, dephos-
phorylation events activate glycogen synthase and inactivate glyco-
gen phosphorylase. Glycogen synthase and glycogen phosphatase
are also allosterically regulated by the level of metabolites including
adenosine phosphate molecules and glucose-6-phosphate [3, 5, 6].
The 5’AMP-activated protein kinase (AMPK) is a heterotri-
meric protein complex that orchestrates important signaling cas-
cades to regulate cellular energy metabolism [7–9]. In general,
upon stress that could be caused by starvation or exercise, AMPK
is activated which induces energy-producing catabolic pathways
including glycogen breakdown. However, when nutrients are plen-
tiful, AMPK is inhibited, inducing energy-consuming anabolic
pathways including glycogen synthesis [7–9]. Specifically, acute
AMPK activation leads to phosphorylation and inactivation of gly-
cogen synthase and a decrease in glycogen content [10–13]. While
this role of AMPK in glycogen metabolism has been widely
accepted, increasing evidence suggest that the chronic activation
of AMPK leads to glycogen accumulation instead of glycogen
degradation [14–16]. AMPK is chronically activated during endur-
ance exercise, which promotes glycogen accumulation in muscles
with training. Accordingly, the constitutive activation of AMPK via
mutations in theγ2 andγ3 subunits leads to the accumulation of58 Elite Possik and Arnim Pause