ATP Equilibrium in Creatine Supplementation

Written By: Alexia Bensoussan and Justin Colon 

This Exemplar will teach the following concepts from the ACS Examinations Institute General Chemistry ACCM:

1. Both physical and chemical changes may occur in either direction (e.g., from reactants to products, or products to reactants).
   • Phase changes are reversible and provide a good example of dynamic equilibrium
   • Interpretation of phase diagrams can be tied to the understanding of equilibrium concepts
2. For chemical and physical processes, the equilibrium state can be characterized via the equilibrium constant.
   • The equilibrium constant can be used in calculations that determine the amount of reactants or products present at equilibrium for a given initial state.
     • The equilibrium state is characterized by a constant, designated K, which provides quantitative information of the extent of a reaction and is related to the ratio of the concentrations of reactants and products
     • The equilibrium constant, K, is a function of temperature.
     • The equilibrium constant, K, incorporates reaction stoichiometry as part of the ratio. 
     • Calculations using equilibrium constants may determine K, or estimate equilibrium concentrations given initial concentrations of a system with a known value of K.

3. When the equilibrium constant is very large or small, products or reactants, respectively, are primarily present at equilibrium. Systems with K near 1 have significant amounts of both reactants and products present.

   • Very large or very small values of the equilibrium constant, K, indicate reactions strongly favoring products (in the former case) or reactants (in the latter).

   • Reactions with very small values of K will have little formation of products, while reactions with very large values of K will proceed nearly completely to products.

4. Gibb’s free energy is a state function that simultaneously calculates entropy for the system and surroundings, and is useful for determining whether or not a process occurs spontaneously.

   • Gibbs free energy is defined in such a way that the calculation of it provides insight into whether a process is spontaneous with a single calculation

   • The Gibb’s free energy is defined in terms of enthalpy and entropy changes; students should be able to consider these components both quantitatively and qualitatively.

5. Macroscopic samples of matter contain so many atoms that they are counted in moles.

   • The mole is defined based on the relative mass scale for atoms, and this results in Avogadro’s number being equal to 6.02 × 10²³

   • The translation between atomic-level understanding and macroscopic understanding is facilitated by the concept of the mole

6. Conversions involving the mole (molar mass, g/mol, mol/# of atoms, etc.) are critical to being able to describe matter at both the particulate level and the macroscopic scale.

   • Quantitative conversions with the concept of the moles are important.

 

What is Creatine?

Creatine is known as a strength building supplement in the fitness industry, all human beings produce certain levels of creatine. Creatine can be naturally introduced in two ways. First, the molecule can be synthesized in the liver with the amino acids, glycine, arginine and methionine. Second, it can be gained through the consumption of meat and fish products. As for creatine supplements, the two most commercialized forms (and the types we will discuss) are creatine monohydrate (CrM) and creatine hydrochloride (CrHCl). These supplements work because ingestion of creatine leads to an increase in skeletal muscle creatine concentration. Studies have also shown that increasing creatine concentration has led to increases in phosphocreatine concentrations.

Figure \(\PageIndex{1}\): Raw Meat https://unsplash.com/photos/YlAmh_X_SsE?utm_source=unsplash&utm_medium=referral&utm_content=creditShareLink

How Does Creatine Work?

Although creatine, specifically CrM, “can be effective as adjuvant therapy to treat muscle wasting diseases, CNS disorders and bone and metabolic disturbances,” (Valenzuela et al. 2019) in this paper, we are focussing on the ATP hydrolysis reaction with creatine for muscle endurance. 

In general, when a muscle contracts and is under tension, it uses the hydrolysis of ATP to release energy. To simplify the process, during ATP hydrolysis, ATP loses one of its phosphate groups, producing ADP and energy. Since we depend on our ATP storage in skeletal muscles during exercise for energy, the concentration of ATP determines the duration of multiple muscle contractions. This suggests that a higher concentration of ATP would allow for more contractions which could lead athletes to exercise harder and over a longer period of time. As ATP is being broken down to produce energy ADP is being resynthesized into ATP. This is where creatine comes in. 

Creatine is already a naturally-occurring molecule in our bodies, yet it is produced in such small amounts. During muscle contractions, the formation of ATP occurs through a mechanism with ADP and phosphocreatine (creatine with an extra phosphate group donated by ATP) reacting together to reform ATP with the help of the creatine kinase catalyst. Whereas muscle contractions cause an increase of creatine in skeletal muscles, skeletal muscle contractions are correlated with a decrease in phosphocreatine concentrations. The opposite effect for phosphocreatine is observed during muscle relaxation. 

The equilibrium reaction is depicted in the text and figure below: 

\[ phsophocreatine + ADP⇔ creatine + ATP \label{ATP Equilibrium} \] See equation \ref{ATP Equilibrium}

Figure \(\PageIndex{2}\): Creatine + ATP equilibrium depicted.

It is important to note that creatine does not directly react with ADP but “there is a pathway by which creatine assists in the resynthesis of ATP.” (Ashford 2008)

It is also important to note that different types of muscle fibers are affected by creatine in different ways. Type one fibers, also known as slow-twitch fibers that are used in long-term aerobic exercise such as running or biking, gain their source of energy primarily from triglycerides rather than ATP. On the other hand, type-II fibers, or fast twitch fibers used in short maximal efforts such as lifting weights, receive 33% more of their energy from ATP compared to slow-twitch fibers (Casey, Greenhaff, 2000)

Creatine Supplementation:

Figure \(\PageIndex{3}\): Creatine Monohydrate Powder ... https://unsplash.com/photos/S9NchuPb79I?utm_source=unsplash&utm_medium=referral&utm_content=creditShareLink

Creatine supplementation becomes significant after saturating the body’s muscles. In order to saturate muscles, there is a loading phase dosage and maintenance dosage. The loading phase consists of 1-2 weeks of a higher dosage of creatine per day, and the maintenance dosage is then taken post-loading phase when an individual ingests a much smaller creatine dosage per day. According to Valenzuela et al. “A loading CM dose of 20–25 g/day divided into 4–5 intakes of 5 g each over 4–6 days followed by a maintenance dose of 3–5 g/day seems to be the most effective protocol to saturate skeletal muscle creatine stores.” These dosages are amounts of creatine that generally work for most people, yet other factors are still considered when deciding maintenance dosage, such as muscle mass.

In some cases, people choose to forego the loading phase and instead ingest a maintenance dosage daily from the start. This means that those individuals will reach their muscular creatine saturation point after much longer than people who undergo a loading phase.

Creatine Breakdown Into Creatinine:

Creatine can’t remain in the body forever. Eventually, it is degraded into the molecule creatinine which is then filtered through the kidneys and released from the body through urination. This degradation of creatine into creatinine is apparent at low pHs. However, at extremely low pHs, such as that of the stomach, creatine’s nitrogen involved in the donation of its lone pairs gains an additional proton from the surrounding acid and thus has no lone pairs to donate. Given that the pH of a human stomach is approximately 2 and a dose of 5 g is administered to an individual, only 0.1g of creatine would be converted to creatinine one hour after ingestion. In total, “about 2% of creatine is converted to creatinine, and both creatine and creatinine are excreted by the kidneys.” (Medical Economics Co; Physicians Desk Reference for Nutritional Supplements 1st ed p.115 2001).

Practice Problem (Equilibrium Constant):

Problem \(\PageIndex{1}\)

Given the reversible reaction for creatine and phosphocreatine at 25ºC and the Delta Gº value of -12.5kj/mol, find the Keq expression and value for this reaction.

\[ phsophocreatine + ADP⇔ creatine + ATP  \nonumber\]

Answer

Work: 

\[ Keq = \dfrac {([Creatine][ATP])} {([Phosphocreatine][ADP])} \nonumber\]

\[ Delta  G^o= -RTln(Keq) \nonumber\]

\[ Delta  G^o = -RTln(Keq) \nonumber\]

\[ (-12.5 J/mol)(1000 J/1k) = -(8.314 J/mol*K)(298 K)ln(Keq) \nonumber\] 

\[ Keq = 155.29 \nonumber\]

 

Explanation: The Keq expression is an equation in which Keq is equal to the product of product concentrations over the product of reactant concentrations. To find the K value, we use delta G = -RTln(K) and substitute values in to solve for K.

Exercise \(\PageIndex{1}\)

Given that a person currently has 0.1 M creatine, 0.3 M ATP, 0.005 M phosphocreatine, and 0.05 M ADP, determine which way the reaction will proceed.

Answer

Work: 

\[ Q = \dfrac {([Creatine][ATP])} {([Phosphocreatine][ADP])}  \nonumber\] 

\[ Q = \dfrac {(0.1M)(0.3M)} {(0.005M)(0.05M)} = 120 \nonumber\]

\[ Q < Keq \nonumber\]

The reaction will proceed in the forward direction.
 

Explanation: We plug in these concentration values into the Keq expression to find Q and determine if its value is higher or lower than the real Keq value. Since it is lower, the reaction proceeds forward.

The goal of creatine is to produce more phosphocreatine and ADP in order to readily form ATP when needed.

Problem \(\PageIndex{3a}\)

Determine the minimum concentration of creatine needed to start producing phosphocreatine and ADP with the same concentrations of ADP, phosphocreatine and ATP as given above.

Answer

Work: 

\[ Q = \dfrac {([Creatine][ATP])} {([Phosphocreatine][ADP])} \nonumber\]

\[ 155.29 = \dfrac {[Creatine](0.3M)} {(0.005M)(0.05M)} \nonumber\]

\[ [Creatine] = or > 0.129M \nonumber\]

 

Explanation: We plug in the Keq value and concentrations of ATP, ADP, and phosphocreatine from Part (2) and solve for the minimum concentration of creatine that would make Q = or > than the Keq value.

Problem \(\PageIndex{3b}\)

How many more grams of creatine (compared to the previous 0.1 M creatine) are needed to begin producing phosphocreatine and ADP? Assume all molecules are dispersed in a total of 1L of body fluid. The volume change from the addition of creatine is negligible. (MM= 147.16 g/mol).

Answer

Work: 

\[ 0.1 mol/L * 1.0L = 0.1 mol Creatine present \nonumber\]

At least 0.129M Creatine is needed

\[ 0.129 mol/L * 1.0L = 0.129 mol  Creatine  needed \nonumber\]

\[ 0.129 mol - 0.1 mol = 0.029 mol  Creatine  added \nonumber\]

\[ 0.029 mol * 147.16 g/mol = 4.27g  Creatine \nonumber\]

4.27 grams of Creatine needs to be added. 

Explanation: We find moles of creatine already in the body from the concentration in Part (2) and the moles of creatine needed to make Q = or > Keq using 1L of fluid. Then, we subtract the moles of creatine already present from the moles of creatine needed to find the moles of creatine that needs to be added. Using the molar mass of creatine given in the question, we convert the moles of creatine needed to be added into grams of creatine.

Problem \(\PageIndex{4}\)

The percent masses in creatine monohydrate and creatine HCl are 87.9% and 78.2% respectively. Find the minimum mass of each creatine that is needed to start producing more phosphocreatine and ADP.

Answer

Work: 

Creatine monohydrate

\[ \dfrac {87.9%} {100%} = 0.879 \nonumber\]

\[ 0.879x = 4.27g ; x = 4.858g \nonumber\]

4.858 grams of Creatine monohydrate is needed

 

Creatine HCl

\[ \dfrac {78.2%} {100%} = 0.782 \nonumber\]

\[ 0.782x = 4.27g ; x = 5.46g \nonumber\]

5.46 grams of Creatine HCl is needed. 

Explanation: We know that 87.9% (.879) of x grams of creatine monohydrate will yield 4.27 grams of usable creatine. We know that 78.2% (.782) of x grams of creatine HCl will yield 4.27 grams of usable creatine. Through algebra, we find the respective x values that tell us how many grams of either creatine monohydrate or creatine HCl would be needed to start producing phosphocreatine and ADP in the body.

Conclusion and Application:

As discussed, creatine allows for more resynthesis of ATP, thus allowing for more prolonged periods of physical exertion. This process reiterates the prevalence of chemistry within metabolic processes. An increased concentration in either products or reactants causes an increase in the production of the other. In this case, the addition of solid creatine, once metabolized, spurs the production of phosphocreatine and ADP. Forcing a chemical equation to proceed toward reactants or products with respect to a set of molecules in the body is attributed to a chemical equation’s equilibrium constant, K, which exists for reversible equations. Through the practice problem, we also reviewed how the Gibbs free energy relates to a specific equation’s equilibrium constant. A negative Gibbs free energy value correlates to an equilibrium constant greater than one, meaning that the chemical equation in context is spontaneous and proceeds on its own. Lastly, the sample problem explored the application of Avogadro’s number and conversions using the molar mass of compounds in order to calculate the mass of a compound needed to cause a specified change within a reaction system or biological mechanism.

While creatine supplementation significantly helps with having more energy, it is not needed for most people as natural levels of creatine are certainly sufficient. Furthermore, creatine supplementation will not greatly benefit individuals who do not regularly expend large amounts of energy. Mostly people who do exercise regularly will exhibit the effects that creatine supplementation has to offer. It is also useful to note that there is a saturation point for creatine, and ingesting excess amounts of creatine will not provide extra added benefits. This is important to know when trying to make a container of creatine last as long as possible before purchasing more creatine. Overall, creatine is a great supplement and there is much to learn about, but connecting its function to different chemistry mechanisms makes it truly fascinating.

 

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References:

1. Ashford, D. Creatine: The Chemistry behind the supplement. https://www.muscleandstrength.com/ar...upplement.html (accessed Nov 9,  2022).

2. Bioenergetics and Biochemical Reaction Types. https://memberfiles.freewebs.com/71/...tions_ch13.pdf (accessed Nov 10,  2022). 

3. Creatine. https://pubchem.ncbi.nlm.nih.gov/com...sm-Metabolites (accessed Nov 9,  2022). 

4. LeBaron, T. (PDF) creatine recommendation report - researchgate. https://www.researchgate.net/publica...ndation_Report (accessed Nov 10,  2022). 

5. Valenzuela, P. L.; Morales, J. S.; Emanuele, E.; Pareja-Galeano, H.; Lucia, A. Supplements with purported effects on muscle mass and strength - european journal of nutrition. https://link.springer.com/article/10...394-018-1882-z (accessed Nov 9,  2022).