Anaerobic Glycolysis

Glycolysis | Muscle Glycogen | Regulation of Glycolysis

Glycolysis

• first step of glycolysis is glucose transport (facilitated diffusion) across the sarcolemma that is accomplished by a specific protein on the plasma membrane-requires insulin during resting states but less insulin is required during exercise
• after glucose enters the muscle, it is immediately phosphorylated in a non-reversible reaction by hexokinase
• primary rate-limiting step of glycolysis is the phosphofructokinase (PFK) reaction where fructose-6-phosphate is phosphorylated to fructose-1,6-bisphosphate
• notice that by this point, 2 ATP have been utilized by the pathway
• the 6-carbon molecule is next split into two 3-carbon molecules, each having a phosphate group
• from an isomerization reaction, DHAP is also formed into PGAL (glyceraldehyde-3-phosphate) so that there are now two identical PGALs

Note: Keep in mind that from this point, all steps are occurring twice with the metabolism of one glucose.

• in the next step, NAD⁺ is reduced to NADH, and, two ADP are rephosphorylated to ATP in two subsequent steps
• final step of glycolysis is formation of pyruvate. At this step, pyruvate forms either into lactate (lactate dehydrogenase, LDH) or enters the mitochondria and the Kreb's cycle
• production of lactate requires the oxidation of NADH to NAD⁺

Muscle Glycogen

Glycogen is basically glucose units linked together into small hard granules stored in sarcoplasm to provide readily-available fuel that can be rapidly metabolized

Glycogenolysis

• a glycosyl (glucose) molecule is split off the glycogen, a Pi is added, and glucose-6-phosphate is formed. Note that this does not require any energy (ATP) input
• during high-intensity exercise, glycogen supplies most of the glucose units
• breakdown of muscle glycogen is controlled by phosphorylase a through a series of events initially started by Ca²⁺ and increased [Pi]
• [Pi] is an important stimulator of glycogenolysis, however, other unknown modulators are involved
• EPI activates adenylate cyclase which stimulates cAMP production and glycogenolysis

+ cAMP, Ca²⁺, ADP, AMP, IMP, Pi

phosphorylase b (inactive) <======> phosphorylase a (active)

-- ATP, G-6-P, H⁺

• activation of phosphorylase a inactivates glycogen synthase

Glycogenesis

• glucose enters the muscle and is phosphorylated (requires an ATP) forming G-6-P
• the phosphate group is removed and the glucose unit linked to the glycogen molecule
• glycogenesis is stimulated by activation of glycogen synthase which is stimulated by insulin and inhibited by Ca²⁺ and cAMP
• generally, glycogen synthase is activated when phosphorylase is inactive and vice versa

Regulation of Glycolysis

adenylate nucleotide energy charge

• Adenine nucleotide energy charge = [ADP] + 2 [ATP] _ X 0.5

[AMP] + [ADP] + [ATP]

• if all adenine is in the form of ATP, the energy charge is 1.0; if all adenine is in the form of AMP, the energy charge is 0.0; energy charge is usually ~0.8

phosphofructokinase (PFK)

• primary rate-limiting enzyme of glycolysis
• changes in [ADP], [AMP], and [Pi] are likely responsible for stimulating PFK with onset of high-intensity exercise
• other modulators take longer to influence PFK because their intracellular changes take longer to occur

Primary Stimulators	Primary Inhibitors
ADP	ATP
Pi	PCr
AMP	H^+
NH4^+	citrate
increased temperature

lactate dehydrogenase (LDH)

• LDH is in competition with the mitochondria for pyruvate, however, some lactate is always formed regardless of whether exercising or not
• LDH inhibited by high energy charge