What is Metabolic Overload? Metabolite Accumulation Explained

Strenuous exercise and progressive resistance training have been confirmed to help promote muscle growth. Specifically, there are different mechanisms that promote muscle growth – one being metabolic overload which in turn leads to metabolite accumulation. 

For the muscles to be able to work, they have to use energy. The rate of energy production has to be greater than the rate of energy consumption in the muscles. Furthermore, energy production in the muscles use a number of substrates – and end up producing several metabolic by-products. Metabolic overload is when the muscles cannot keep up with the rate of energy consumption. This also leads to metabolite accumulation which is the saturation of metabolic by-products in the muscles which hamper the muscle’s ability to perform, eventually leading to fatigue.  

Muscular Energy Production and Utilization  

The primary energy compound or energy currency used in the body is adenosine triphosphate (ATP). This compound is used to fuel hundreds of chemical reactions that cannot take place spontaneously inside the cell.  

A simple example of ATP use would be for active transport. While some products can easily pass through a cell due to their size and structural properties (e.g., oxygen, water, etc.), other products require channels that use energy to allow passage through the cell membrane (e.g., glucose, amino acids, minerals, etc.).  

Another main function of ATP is to fuel the contraction of muscle cells. In essence, muscle contraction and movement are initiated by a signal cascade from the brain to the muscle. This uses the neurotransmitter acetylcholine which releases sodium ions into the muscle area an individual wants to move. If the signal is strong enough, then channels running along muscle fibers will open and will release calcium ions.  

The sarcomere, or the basic contracting unit of the muscle, is distinguished by two filamentous proteins: actin and myosin. These two filamentous proteins structurally prefer to slide over each other and contract (sliding filament theory), but regulatory proteins troponin and tropomyosin inhibit this interaction.  

With the influx of calcium ions, the regulatory proteins then allow actin and myosin to interact and with a steady supply of ATP, the two filaments slide across one another. This causes muscles to contract and produce movement.    

While the muscles require a great deal of energy in the form of ATP, they are not specially designed to store a large amount. To compensate, the muscles make use of three different systems to produce ATP locally. These systems use aerobic respiration, anaerobic respiration, and creatine phosphate.  

Aerobic respiration occurs in the mitochondria. Colloquially called “the powerhouse of the cell,” muscle fibers are abundant with mitochondria. Aerobic respiration can be simplified as the conversion of one molecule of glucose and six molecules of oxygen into six molecules of carbon dioxide, six molecules of water, and energy (in the form of ATP). Despite a simplified equation, aerobic respiration is composed of several different pathways that can eventually take one molecule of glucose and have a theoretical maximum production of 38 molecules of ATP. 

However, aerobic respiration requires oxygen – a molecule that is often deficit during strenuous physical activity. Thus, the body has also developed a way to produce energy without oxygen – also called anaerobic respiration. Unfortunately, anaerobic respiration is not as efficient as aerobic respiration which means one molecule of glucose does not create as much ATP as aerobic respiration. Furthermore, anaerobic respiration creates lactic acid as a by-product.  

Lastly, the muscles can create new ATP by using creatine phosphate. Creatine is especially concentrated in the skeletal muscles for this purpose. Creatine gets phosphorylated inside the mitochondria and becomes creatine phosphate. The muscle then keeps a pool of creatine phosphate until it reaches an ATP deficit. Once used, ATP loses one phosphate group and becomes adenosine diphosphate (ADP). Phosphorylated, the creatine phosphate can donate its phosphate group to ADP to recycle ADP back into ATP.  

Metabolic Overload 

Despite the different ways muscles can produce energy for work, sufficient use such as strenuous physical activity can not only deplete the existing pool of ATP but outmatch the rate by which these systems produce energy. Having a greater rate of energy use, the muscles then reach a point of metabolic overload. 

Trainers and athletes often aim to reach this point because this is one of the three mechanisms that can promote muscle growth (i.e., the other two being mechanical stress and muscle damage). Metabolic overload is a physiological process that influences different signaling pathways which eventually leads to certain muscle adaptations such as cell swelling which can also lead to hypertrophy – the enlargement of muscles due to the increase in cell size rather than cell number.  

Depleting the energy pool, metabolic overload can then lead to metabolite accumulation.    

Metabolite Accumulation 

As mentioned above, there are three different systems that produce energy in the muscles. Aside from ATP, these systems also produce metabolites (by-products of metabolic processes). At a certain rate, the body can handle these by-products so that they do not inadvertently affect the body. However, at metabolic overload, these by-products can build up which leads to metabolite accumulation.  

Metabolite accumulation eventually leads to muscle fatigue and an inability to perform. As the body is run by chemical reactions, it should be noted that these chemical reactions are highly receptive to the environment and require certain conditions to occur. Metabolite accumulation is not ideal because it makes the environment unfavorable for certain chemical reactions to occur.  

Here are some metabolites and the consequences of their accumulation:

Acidity: Lactic Acid, Carbon Dioxide, and Hydrogen Ions 

An organic compound, lactic acid is a by-product of anaerobic respiration. Structurally, it has a terminal carboxylic acid group and a hydroxyl group located in the second position. According to its acidity, lactic acid is ten times more acidic than acetic acid (vinegar).  

The main concern of lactic acid accumulation is its acidity. While not especially neutral or basic, the normal resting acidity level (pH) of the skeletal muscle is around 5.99-7.38 – a range that significantly decreases (acidifies) due to intense exercise. 

Many enzymes and proteins in the body have an optimum pH by which they can operate. Given the severe change in acidity, lactic acid accumulation then presents a problem to the surrounding enzymes and cellular processes in the muscles.  

Aside from lactic acid, a major contributor to the acidity of the muscles is hydrogen ions. These are by-products of multiple cellular processes in the muscles. It is estimated that the dominant contributor of hydrogen ions is the decrease in strong ion difference, while the other processes that contribute to hydrogen ions include the breakdown of phosphorylated creatine, the increase in apparent proton dissociation constant, and the partial pressure of carbon dioxide.  

Another metabolite that increases acidity is carbon dioxide. As mentioned above, carbon dioxide is a by-product of aerobic respiration when glucose and oxygen are converted into carbon dioxide, water, and energy. However, carbon dioxide is especially short-lived as it is immediately carried out by the blood and into the lungs for exhalation. While acidic, no studies have found that metabolite carbon dioxide contributes to muscle fatigue. 

Increased acidity in the muscles inhibits a certain enzyme called phosphofructokinase. This is an important enzyme that plays a crucial role in glycolysis or the breakdown of glucose into pyruvic acid. Glycolysis is one of the many steps involved in cellular respiration (both aerobic and anaerobic) and the inhibition of phosphofructokinase severely hampers the muscle’s ability to produce ATP.  

Acidity in the muscles is so problematic that the body has developed specific buffer systems to try and maintain the normal operating pH levels in the muscles. Carnosine, the product of beta-alanine and histidine, is one of these physiochemical buffers that the body utilizes. Numerous studies have shown that beta-alanine supplementation was able to increase carnosine pools in the muscles, thus leading to improved physical performance and a reduction in muscle fatigue.      

Reduction in Contractile Force: Magnesium Ions, ADP, and Inorganic Phosphates 

Aside from metabolites acidifying the muscles, another effect certain metabolites can cause is the reduction in contractile force. Consequential reduction in contractile force can happen due to different causes rooted in different metabolites accumulating.  

For example, during intense exercise, magnesium ions (Mg²⁺) can accumulate. Magnesium ions naturally act as the antagonist of calcium ions during muscle contraction. As calcium ions are released into the muscle fibers which activate contraction, magnesium stimulates the re-uptake of these calcium ions back where they came from. This allows the action to be repeatable since if the calcium does not go back, then the muscles will be stuck in a contracted position.  

However, magnesium ions have been observed to accumulate during intense exercise which can eventually lead to reduced contractile force since excessive magnesium ions will prompt calcium ions to be inaccessible to the muscle proteins.  

ADP and inorganic phosphates (the phosphate group that is released during the conversion of ATP to ADP) have also been observed to reduce contractile force. As ATP is heavily used, ADP and inorganic phosphates accumulate which have been studied to slow the rate of muscle relaxation and reduce calcium release into the sarcomere.  

Final Thoughts

While metabolic overload and metabolite accumulation can confer deleterious effects on the body and subsequent soreness, they can also provide some benefits. Professional athletes and trainers are equipped with the knowledge to discern up to which point they can aim for metabolic overload and metabolite accumulation to maximize benefits while minimizing harm.