Hypertrophy Mechanisms [3/3] – Metabolic Stress [1/2]

Metabolic stress can also have a significant hypertrophic effect. Metabolic stress refers to metabolite accumulation from the anaerobic glycolysis for ATP production. Metabolites such as lactate, creatine, and hydrogen ions build up (1,2,3), and cause a substantial metabolic stress. There’s increases in blood lactate, intramuscular lactate, glucose and glucose-6-phosphate (1,3,4) with a significant impact on anabolic processes (5).


Glycolysis harvests chemical energy by oxidizing glucose to pyruvate. Glucose is oxidized to form two molecules of pyruvate (the ionized form of pyruvic acid.) Most of the energy remains stockpiled in the two molecules of pyruvate.

Cells use molecules called electron carriers as oxidizing agents. The most important is a compound called nicotinamide adenine dinucleotide (NAD). NAD exists as NAD+, which is positively charged, NADH which is a reduced form. The H in NADH is an added hydrogen ion, which comes along when the molecule picks up two additional electrons.

NAD traps electrons from glucose through enzymes called dehydrogenases. Dehydrogenases remove hydrogen atoms from organic substrates (glucose = C6H12O6). Dehydrogenases essentially remove two electrons and two protons (the same as two hydrogen atoms) from the substrate. Two of these electrons and one proton is delivered to the NAD+ molecule (forming NADH), and the other proton is released as a hydrogen ion. Thus, for every 2 hydrogen atoms taken from glucose one hydrogen ion is released. (There are also other reactions releasing protons)

Electrons released from the oxidation of glucose form 2 molecules of NADH. Glycolysis occurs whether or not O2 is present. If molecular oxygen is present, pyruvate and NADH are oxidized (pyruvate oxidation) and enters the mitochondrion, where the oxidation of glucose is completed.

However, fermentation and anaerobic respiration enable cells to produce ATP without the use of oxygen. Fermentation is an extension of glycolysis, but there must be a sufficient supply of NAD+ which is recycled from NADH under aerobic conditions. An anaerobic alternative is to transfer electrons from NADH to pyruvate, which forms lactate.

Glycolysis is stimulated by muscular contraction itself. The more rapid the contractions the faster the pathway will run. The speed of the pathway is controlled by the enzyme phosphofructokinase.

Lactic acid

Glycolysis starts with either glucose or glycogen, and ends with pyruvate after 10 or 9 steps respectively. Whatever happens with pyruvate is another process other than glycolysis.

Lactic acid is a by-product of glycolysis (6) and is highly correlated to the release of testosterone and growth hormone (7,8,9), however transient rises have a negligible effect on hypertrophy (10,11). The lactic acid energy system is maximized when doing 30-120 seconds of work, the more active the enzyme lactate dehydrogenase is the greater the buildup of lactate will be.

During lactic acid fermentation pyruvate is reduced directly by electrons from NADH to form lactate (lactate is the ionized form of lactic acid.) Human muscle cells make ATP by lactic acid fermentation when oxygen is scarce. This occurs during strenuous exercise, muscles may be breaking down sugar by glycolysis so quickly that NADH cannot be oxidized fast enough, at this point cells switch from aerobic respiration to anaerobic (fermentation).

Blood Lactate Accumulation

With inadequate oxygen supply and utilization, all of the hydrogens formed in rapid glycolysis fail to oxidize, then pyruvate converts to lactate in the chemical reaction: Pyruvate + 2H >Lactate.

Lactate forms as excess hydrogens produced during glycolysis attach to pyruvate. Lactate is cleared by being transformed to pyruvate in the cytoplasm to enter the mitochondria (Fig. 1). In the mitochondria pyruvate converts to acetyl-CoA for entry to the citric acid cycle for aerobic energy metabolism.

Lactate formation continues to increase at higher levels of exercise intensity when active muscle cannot meet the additional energy demands aerobically.

Slow twitch and fast twitch muscle fibers have different mitochondria densities and thus different clearance rates for lactate. Slow twitch have more mitochondria than fast twitch, thus fast twitch fibers have a lesser ability to clear the lactate produced, promoting lactate build up.

The speed of a reaction (lactate production) is directly correlated to the catalytic rate of the enzyme controlling the process – lactate dehydrogenase. This enzyme is responsible for the production of lactate from pyruvate, which transfers two hydrogens to pyruvate to form Lactic Acid. The faster glycolysis takes place the more rapid the accumulation of lactic acid will be (12). An increase in pyruvate will ultimately lead to an increase in lactate accumulation.

Other uses for lactate

Most of lactate ends up being oxidized in the critic acid cycle inside the mitochondria. However, some lactate is released into the blood and enters the liver where it is converted back to pyruvate, and synthesized back to glucose through the Cori cycle’s gluconeogenic reactions. This glucose from lactate can return to skeletal muscle for energy metabolism or synthesized to glycogen for storage.


The greater acidic environment may mediate an increased adaptive hypertrophic response by increasing fiber degradation and greater stimulation of sympathetic nerve activity (24).

However, it’s not the lactate that causes acidosis in the cell, there is no biochemical support for lactate production causing acidosis (25,26). In fact, lactate production retards, not causes, acidosis. Acidosis is caused by reactions other than lactate production, such as proton accumulation (hydrogen ions) in the cell.

Protons are used for mitochondrial respiration (oxidative phosphorylation). When the exercise intensity increases beyond steady state, proton release increases and causes acidosis.  Metabolic acidosis is caused by an increased reliance on nonmitochondrial ATP turnover (25).

The proton release from glycolysis is associated with the hydrolysis of ATP in the hexokinase (becoming glucose 6-phosphate) and phosphofructokinase reactions, as well as the oxidation of glyceraldehyde 3-phosphate in the glyceraldehyde 3-phosphate dehydrogenase reaction (25). These are the released protons relevant for acidosis.

The use of glycogen as the primary substrate (glycogenolysis) differs from glycolysis in bypassing the first reaction and thus shares the remaining nine reactions. The proton release from glycolysis differs depending on whether glucose or muscle glycogen is used to form G6P and fuel glycolysis (25).

For the production of 2 pyruvate, there is a net release of 2 protons when glucose is the source of glucose 6-phosphate (G6P), and 1 proton when glycogen is the source. Using glycogen as the source of G6P, as opposed to blood glucose, is less acidifying to muscle during intense exercise (25).

Cell Swelling

Metabolic stress and moderate repetition sets augment the blood pump, which can facilitate myofibrillar hydration (13). A pump results through the collapsing of veins as the arteries continue to bring blood to the muscles, causing a flow of blood to go back and hydrate the tissue. This process can inhibit proteolysis (protein catabolism), and augment protein anabolism or synthetic rates (14,15,16).

Cell swelling inhibits proteolysis and stimulates protein synthesis, and cell shrinkage does the opposite. Cell swelling is an anabolic signal and cell shrinkage is a catabolic signal (16).


Ischemia is a restriction in blood supply to tissues, causing a shortage of oxygen and glucose needed for biological work. Muscle ischemia also causes metabolic stress, and even more so when added to anaerobic glycolysis (1,17,18). This metabolic stress increase the hormonal milieu, cause cell swelling, free-radical production, and increased activity of growth-oriented transcription factors (1,19,20,21).


Hypoxia is a reduction in oxygen supply. Resistance training under systemic hypoxia leads to greater increases in muscle mass (22), muscular endurance and angiogenesis (new blood vessels) in the skeletal muscle (23). Vascular endothelial growth factor (VEGF) is known to play a critical role in increasing angiogenesis. There’s increases in plasma VEGF concentrations, and increased capillary-to-fiber ratio - systemic hypoxia increases muscle capillarization (23).

Hypoxia increase lactate accumulation and reduce acute lactate clearance rate (1,22), contributing to increased cell swelling, which has been shown to upregulate protein synthesis (16).

Ischemia produces hypoxia, however hypoxia can take place without ischemia, for example in high altitude training.

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