Table of Contents
In Lesson 1 we discussed how the body generates movement using the nervous and musculoskeletal systems. We also discussed the physiologic adaptations that occur with strength training to allow these systems to better accommodate new stresses over time. In this lesson we will discuss how the body generates energy to fuel skeletal muscle contractions. We will also discuss the physiologic adaptations that occur with aerobic training to make this process more robust.
Overview of energy productionRegarding skeletal muscle contractions, there are several systems involved in energy production and the removal of metabolic waste products. In skeletal muscle various biochemical reactions take place to generate adenosine triphosphate (“ATP”). The respiratory and cardiovascular systems collectively transport supplies to the skeletal muscle for ATP generation.
Note: Similar to the last lesson, much of the information in this lesson provides an overview of physiology, and some may not find this interesting or practical to go through in detail. Feel free to skim through the lesson to the “Summary of energy production” section if desired; you will still be able to go through the course without reading the rest and can refer to the remaining material for clarity if needed.
Adenosine triphosphate (“ATP”) production
We learned in Lesson 1 that ATP is required for skeletal muscles to contract. Thus, it is crucial for skeletal muscles to have sufficient ATP to fuel the exercise we want to perform. With the exception of the first several seconds of activity (see note below), muscle fibers actively produce ATP to fuel contractions.
Note: At baseline there is ATP present within muscle that can be utilized to fuel skeletal muscle contractions. We learned in Lesson 1 that cross bridge formation converts ATP into adenosine diphosphate (“ADP”) and inorganic phosphate (“Pi”). The enzyme creatine phosphokinase within muscle fibers uses phosphocreatine (PCr) to convert ADP + Pi back into ATP. There is enough PCr stored to last for up to ~2-7 seconds; this is generally how long someone can perform a full sprint prior to slowing down. Subsequently, it takes ~1 minute for 50% of PCr to replenish and ~5-7 minutes for 95-100% recovery.(Kraemer, 2012) Consuming creatine supplements generates larger PCr stores; this allows one to sustain peak intensity of movement for slightly longer. If one is performing exercise for >7-10 seconds this requires additional ATP; how this is generated is discussed below.
Note: Unless otherwise stated I took all of the images in this lesson from Wikipedia.
The schematic below shows the primary means by which cells generate ATP. Knowing all of the details is not necessary or helpful. The main points include:
- the primary substrate for energy production is glucose
- glycolysis generates a small amount of ATP (2 ATP per molecule of glucose) without the use of oxygen (thus this is “glycolytic” or “anaerobic” energy production)
- after glycolysis cells transport the breakdown products of glucose (two molecules of pyruvate) into mitochondria, convert them into acetyl-CoA, and metabolize them through the Krebs Cycle – these metabolic steps generate molecules of NADH & FADH2
- the NADH & FADH2 provide energy for the electron transport chain that culminates in ATP production
Note: Through separate biochemical steps fatty acids undergo beta-oxidation to generate acetyl-CoA, NADH, and FADH2. These molecules function identically to the ones generated through glycolysis. One molecule of fatty acid actually generates significantly more ATP than one molecule of glucose. However, beta-oxidation takes longer than glycolysis. For this reason, glycolysis is the primary source of ATP production at higher exercise intensities.
The electron transport chain extracts electrons from the NADH & FADH2 and generates a gradient of hydrogen ions across the membrane. This gradient powers ATP synthase to generate more ATP from ADP + Pi; in this manner 1 glucose molecule can generate >30 ATP. Importantly, oxygen functions to receive electrons and combines with hydrogen to form water. Thus, oxygen is crucial for the steps in the mitochondria. As a result, this is considered “aerobic” or “oxidative” energy production.
Note: Without sufficient oxygen the pyruvate undergoes fermentation, yielding lactic acid. This happens more readily with higher intensity exercise since glycolysis still occurs for anaerobic energy production even if the mitochondria lack oxygen to utilize the pyruvate. Then the “Cori cycle” occurs and transports lactic acid to the liver where it undergoes gluconeogenesis to generate more glucose. Glucose then moves back through the bloodstream to working muscle.
Additionally, glycolysis occurs more quickly than the Kreb’s cycle and electron transport chain steps. Thus, when activity is initiated and the phosphocreatine stores are depleted, glycolysis provides the majority of the ATP for the first 45-60 seconds via anaerobic energy production. Glycolysis does not continue to supply the majority of ATP indefinitely due to a limited supply of glucose; remember, anaerobic metabolism yields only 2 ATP per molecule of glucose while aerobic metabolism yields >30. Additionally, increased intramuscular acidity from lactic acid will eventually limit the rate of glycolysis.
The bloodstream transports a small amount of glucose to muscle. This is either from glucose we eat directly or glucose generated in the liver from other substrates (via gluconeogenesis). However, most glucose for skeletal muscle energy production derives from glycogen. Glycogen is a storage form of glucose present primarily within muscle and the liver. It is composed of a central glycogenin protein surrounded by potentially many thousands of glucose molecules. A schematic is shown on the right. Glycogen is stored with water in the body in a 1:3 to 1:4 ratio.
The fatty acids used in beta-oxidation come from intramuscular triglycerides (IMTG, fatty acid stores within muscle – this is a relatively small contribution) and adipose tissue. Glycogen is the primary fuel source for higher intensity physical activity because:
- it is more readily accessible within muscle than glucose or fatty acids (which require blood transport)
- beta-oxidation of fatty acids from the bloodstream or intramuscular triglycerides takes longer in general
For lower intensity activity a higher proportion of energy comes from fatty acids; this spares muscle glycogen in case it is needed for higher intensity activity.
The image below summarizes the primary sources of substrates for ATP production.
Note: The above provides an overview of skeletal muscle energy production. For a more detailed explanation of how this changes at different exercise intensities, please read (Hargreaves and Spriet, 2020).
Tip: Outside of competitive athletes and individuals attempting to maximize performance, considering different strategies to maximize energy supply is unnecessary. Additionally, please understand:
- Fat is maximally utilized for energy production at moderate exercise intensities of ~65% VO2 max (VO2 max is described below).(Alghannam, 2021)
- Carbohydrate sources are increasingly used at higher intensities for ATP production.
- Thus, the contribution of fat relative to carbohydrate for energy production decreases at higher exercise intensities.
- However, this only describes what happens while exercising, not the rest of the time during the day when you are not exercising.
- Therefore, manipulating exercise intensity to alter energy utilization (ie, burning fat vs carbohydrate) with the hope that this will yield a significant fat loss benefit is not worthwhile.
I emphasized in the nutrition and weight management course that the total caloric deficit is key for weight loss; whether our body primarily uses carbohydrates or fats to fuel exercise sessions does not matter. Therefore, I advise you to choose a nutritional approach that leads to consistency and good performance with your exercise sessions, and do not design your exercise sessions for the purpose of primarily utilizing carbohydrate vs fat stores for energy.
The respiratory systemSkeletal muscles require oxygen for aerobic energy production; therefore, our body is well-designed to transport oxygen from the air we breathe to our muscles. When we breathe, air flows through our nose or mouth into our trachea. The trachea then splits into a left and right bronchus. This then continues to split (similar to branches on a tree) into smaller bronchi, then bronchioles, and finally terminate in alveoli. The alveoli are essentially very tiny sacs that fill with air. The capillary beds, very tiny blood vessels, are on the other side of the alveoli, and oxygen diffuses across the alveoli into our blood stream. The image below shows the structure of the lungs and the approximation of alveoli with capillaries. The blue pulmonary artery has deoxygenated blood that branches into the blue capillaries. After oxygen diffuses into the capillaries they appear red in the image. The capillaries with oxygenated blood coalesce into pulmonary veins.
The heartDeoxygenated blood returns from the body to the right atrium of the heart. Subsequently this flows through the right ventricle to the pulmonary artery where it goes to the lungs. Oxygenation occurs (shown above) and the blood returns to the left atrium of the heart through the pulmonary veins. After this the blood moves to the left ventricle which pumps it through the aorta to the rest of the body. This is depicted in the next two images.
The heart alters overall blood flow through two primary mechanisms:
- its stroke volume (“SV”, the amount of blood pumped every time the heart contracts)
- its heart rate (“HR”, the frequency the heart contracts, typically denoted per minute)
Both SV and HR increase when we exercise to deliver more oxygen to muscles and remove metabolic waste products. This increases the overall cardiac output (“CO”), defined as:
CO = SV * HR
HR increases by up to a factor of 3-4 during exercise while SV increases by close to a factor of 2; this leads to a large increase in blood flow when needed to supply working muscle.(Vega, 2017)
The circulatory system
The oxygenated blood is transported throughout the entire body via the aorta, arteries, arterioles, and then capillaries. Oxygen diffuses into all metabolically active tissue. Subsequently, deoxygenated blood returns to the heart through the capillaries, venules, veins, and vena cavae. This is depicted in the two images below.
Note: As shown in the image above the arteries and veins have smooth muscle. This is different from skeletal muscle and this smooth muscle allows the arteries and veins to constrict or dilate (called “vasoconstriction” & “vasodilation”, respectively). When we exercise the blood vessels that supply skeletal muscle vasodilate to allow increased blood flow and hence increased oxygen delivery as well as removal of metabolic waste products.
Summary of energy production
ATP is the source of energy to fuel skeletal muscle contractions. A small amount of ATP resides within cells at baseline and can be recycled for ~7 seconds by phosphocreatine. Beyond this, anaerobic ATP production via glycolysis increases very quickly to fuel exercise for 60-90 seconds or so. During this time aerobic energy production increases, contributing the majority of energy supply beyond ~1 minute. Over longer periods at higher intensities glycogen provides most of the glucose for glycolysis. However, with prolonged endurance events fatty acid beta-oxidation plays a larger role; this is supported by gluconeogenesis in the liver and the absorption of any nutrients (primarily glucose) that are consumed during the event. Ultimately, aerobic energy production relies upon oxygen delivery to the working muscles, and this is dependent upon the cardiovascular and respiratory systems.
Aerobic training adaptations
Aerobic training is known to stimulate several changes in the body. This activates several genes & pathways including PGC-1α, citrate synthase, and p53, among others, that influence mitochondria.(Hughes, 2018) Overall, these gene pathways increase mitochondrial biogenesis and activity within individual mitochondria.(Granata, 2018) Additionally, regular training upregulates pathways involved in beta-oxidation, the Kreb’s cycle, the electron transport chain, and lactate clearance.(Hawley, 2018) Glucose transporter expression in skeletal muscle increases, which improves insulin sensitivity and increases energy utilization.(Farrell, 2021) Altogether, this allows us to generate and utilize more ATP, which improves our aerobic training performance. Some of these improvements occur relatively quickly, with studies showing >25% increases in mitochondrial content within 6-7 high-intensity or sprint interval sessions.(MacInnis, 2017)
Over a longer time period, weeks-to-months, skeletal muscle capillary density increases and allows greater blood flow and hence oxygen delivery to working muscles.(MacInnis, 2017) Blood and plasma volume increase within weeks and maximal stroke volume increases within months. Even the heart itself may enlarge in a positive way; unlike pathological heart failure this is not considered dangerous and is generally reversible.(Vega, 2017; Moreira, 2020; Seo, 2020) Beneficial changes lead to increases in left ventricular end-diastolic volume (increasing the amount of blood the heart can pump at one time) and ventricular wall thickness as well as slowing of the heart rate with an increase in heart rate variability.(Sanchis-Gomar, 2021) Ultimately, cardiac output increases, as does arterial diameter and blood oxygen-carrying capacity.(Farrell, 2021) This increased blood flow not only delivers more oxygen, key for ATP production, but also allows metabolic byproducts such as lactate to be carried away from the working muscles more readily.
With the increased capacity for blood flow to tissues, and the increased ability of mitochondria to utilize the oxygen they receive, this leads to an increase in an individual’s capacity to utilize oxygen and perform endurance activity.
Note: The term “VO2 max” describes an individual’s maximum capacity to utilize oxygen for exercise. This describes the maximum volume of oxygen that one can transport per unit time (typically per minute). Additionally, this can be denoted as an absolute number or normalized to a person’s body weight (typically in kilograms). All of the above systems interact to influence one’s VO2 max, and the relative contribution of different systems vary as one ages.(Valenzuela, 2020) A higher VO2 max generally indicates more advanced endurance capability and a higher level of cardiorespiratory fitness.
When performing interval training and going “all out”, one commonly exercises beyond their VO2 max. This is due to the contribution of anaerobic energy production, as VO2 max only refers to aerobic energy production utilizing oxygen.
Other adaptations distinct from the energy production systems occur as well.(Hughes, 2018) For example, the stiffness of the muscle-extracellular matrix-tendon unit increases, allowing greater storage and release of elastic energy. For example, when running this leads to less energy dissipation into the ground and the elastic energy propels us forward. Another adaptation relates to movement economy; increased training leads to more efficient motor patterns and skeletal muscle efficiency. Consequently, this decreases the energy cost for a given amount of work.
Note: While aerobic training can significantly increase one’s VO2 max, it does not always do this. Additionally, at times the improvement in endurance performance is much greater than expected based on the observed increase in VO2 max.(Kramer, 2020) This likely occurs in part due to additional physiologic adaptations distinct from energy production. However, there is also evidence that mitochondrial volume and function can increase without an increase in VO2 max. Perhaps this allows the body to shift to using fat as a greater source of fuel during exercise while sparing muscle glycogen and decreasing lactate production.
The main point is that while VO2 max is a good marker of cardiovascular fitness, it is not always the limiting factor for endurance performance, and physiologic adaptations can occur to benefit endurance performance without directly influencing VO2 max.
Example: It is easy to visualize improved movement economy over time when watching a toddler learn to walk. Initially toddlers wobble a lot and fall frequently. However, with continued practice they improve and become much more efficient. Similarly, this process occurs with regular aerobic training, and as one becomes more efficient they will burn fewer calories for the same total volume of work.
In this lesson we discussed the basic aspects of energy production to fuel skeletal muscle contractions. Initially the body can rely on ATP & phosphocreatine stores within muscle and very quickly generate further ATP with anaerobic energy production via glycolysis. When exercise is maintained beyond one minute or so the aerobic energy production pathways will begin to contribute the majority of the ATP. Importantly, as one continues to perform endurance activity and aerobic training many physiologic adaptations occur to make oxygen delivery and energy production more robust.
While the first two lessons have shown there are several adaptations that occur to help increase one’s exercise performance, there are also many health benefits of exercise as well. In the next lesson we will go over the official exercise guidelines and the health benefits that accrue when following or even exceeding them.
- Alghannam AF, Ghaith MM, Alhussain MH. Regulation of Energy Substrate Metabolism in Endurance Exercise. International Journal of Environmental Research and Public Health. 2021; 18(9):4963. https://doi.org/10.3390/ijerph18094963
- Farrell C, Turgeon DR. Normal Versus Chronic Adaptations To Aerobic Exercise. 2021 Jul 15. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 34283432.
- Granata C, Jamnick NA, Bishop DJ. Training-Induced Changes in Mitochondrial Content and Respiratory Function in Human Skeletal Muscle. Sports Med. 2018 Aug;48(8):1809-1828. doi: 10.1007/s40279-018-0936-y. PMID: 29934848.
- Hargreaves M, Spriet LL. Skeletal muscle energy metabolism during exercise. Nat Metab. 2020 Sep;2(9):817-828. doi: 10.1038/s42255-020-0251-4. Epub 2020 Aug 3. Erratum in: Nat Metab. 2020 Sep 10;: PMID: 32747792.
- Hawley JA, Lundby C, Cotter JD, Burke LM. Maximizing Cellular Adaptation to Endurance Exercise in Skeletal Muscle. Cell Metab. 2018 May 1;27(5):962-976. doi: 10.1016/j.cmet.2018.04.014. PMID: 29719234.
- Hughes DC, Ellefsen S, Baar K. Adaptations to Endurance and Strength Training. Cold Spring Harb Perspect Med. 2018 Jun 1;8(6):a029769. doi: 10.1101/cshperspect.a029769. PMID: 28490537; PMCID: PMC5983157.
- Kraemer SJ, Looney DP. Underlying Mechanisms and Physiology of Muscular Power. Strength and Conditioning Journal. 2012 December;34(6):13-19 doi: 10.1519/SSC.0b013e318270616d
- Kramer A. An Overview of the Beneficial Effects of Exercise on Health and Performance. Adv Exp Med Biol. 2020;1228:3-22. doi: 10.1007/978-981-15-1792-1_1. PMID: 32342447.
- MacInnis MJ, Gibala MJ. Physiological adaptations to interval training and the role of exercise intensity. J Physiol. 2017 May 1;595(9):2915-2930. doi: 10.1113/JP273196. Epub 2016 Dec
- Moreira JBN, Wohlwend M, Wisløff U. Exercise and cardiac health: physiological and molecular insights. Nat Metab. 2020 Sep;2(9):829-839. doi: 10.1038/s42255-020-0262-1. Epub 2020 Aug 17. PMID: 32807982.
- Sanchis-Gomar F, Lavie CJ, Marín J, Perez-Quilis C, Eijsvogels TMH, O’Keefe JH, Perez MV, Blair SN. Exercise Effects On Cardiovascular Disease: From Basic Aspects To Clinical Evidence. Cardiovasc Res. 2021 Sep 3:cvab272. doi: 10.1093/cvr/cvab272. Epub ahead of print. PMID: 34478520.
- Seo DY, Kwak HB, Kim AH, Park SH, Heo JW, Kim HK, Ko JR, Lee SJ, Bang HS, Sim JW, Kim M, Han J. Cardiac adaptation to exercise training in health and disease. Pflugers Arch. 2020 Feb;472(2):155-168. doi: 10.1007/s00424-019-02266-3. Epub 2019 Apr 23. PMID: 31016384.
- Valenzuela PL, Maffiuletti NA, Joyner MJ, Lucia A, Lepers R. Lifelong Endurance Exercise as a Countermeasure Against Age-Related [Formula: see text] Decline: Physiological Overview and Insights from Masters Athletes. Sports Med. 2020 Apr;50(4):703-716. doi: 10.1007/s40279-019-01252-0. PMID: 31873927.
- Vega RB, Konhilas JP, Kelly DP, Leinwand LA. Molecular Mechanisms Underlying Cardiac Adaptation to Exercise. Cell Metab. 2017 May 2;25(5):1012-1026. doi: 10.1016/j.cmet.2017.04.025. PMID: 28467921; PMCID: PMC5512429.