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Superhero physiology: The case for Captain America

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 Adv Physiol Educ 41: 16 –24, 2017;
doi:10.1152/advan.00106.2016.

A PERSONAL VIEW

Superhero physiology: the case for Captain America

Stanley P. Brown, JohnEric W. Smith, Matthew McAllister, and LeeAnn Joe
Department of Kinesiology, Mississippi State University, Mississippi State, Mississippi
Submitted 8 July 2016; accepted in final form 20 December 2016

Brown SP, Smith JW, McAllister M, Joe L. Superhero physiol- superhero status (30). In fantastic literature, superheroes gen-
ogy: the case for Captain America. Adv Physiol Educ 41: 16 –24, erally gain their abilities in many and varied ways, usually as
2017; doi:10.1152/advan.00106.2016.—Using pop icons in the sci- an accidental encounter with chemicals, radiation, or some
ence classroom represents a creative way to engage often-distracted
agent of otherworldly origin.
students in a relevant and, perhaps more importantly, fun way. When
the pop icon is as universally known as Captain America, the peda- In his cinematic origin story, Captain America was also
gogical stage is set. However, when the movies can also be employed given his abilities through mysterious experimentation. As
to link dramatic references to the science concepts at hand, we may portrayed in the 2011 movie Captain America: The First
have a very powerful tool by which linkages between fiction and Avenger (Marvel Studios), Steve Rogers is injected with the
science can be forged. In this regard, Captain America’s performances super soldier serum and exposed to Vita-Rays. The result is a
in several movies to date can be used to explain actual science. transformation from weakling to superhero. One example of
Granted, script writers and movie directors may or may not be his new capabilities around which this article is based came in
interested in whether the physical performances they depict can be the 2014 film Captain America: The Winter Soldier (Marvel
explained, but that is irrelevant. The point is to make a connection
using science to explain how the superhero can run faster, jump
Studios). Cap is shown performing what for him is an easy
higher, or lift more than is humanly possible. If a teachable moment training run of 13 miles in half an hour. This example and
has occurred and an important concept has been communicated, the statements made in various other Marvel Studio productions
educator has accomplished his or her job well. are used as a backdrop as we seek to give a scientific expla-
nation for the abilities displayed on film.
popular culture; messaging; science; education; superheroes
But why should the thoughtful inquirer of science think
about these fictional characters? Surely, the answer must be,
THE IDEA OF THE FANTASTIC has a long literary history, going back what better way to engage the imagination of today’s oft-
to ancient times when writers of myth and legend “recorded” distracted student than by considering how superhuman feats
the feats of their gods and demigods. In a similar fashion, can be, at least partially, illumined via actual science (36)? A
fantasy novelists of the 19th and 20th centuries have had their body of literature has developed in the field of science peda-
own influence on the larger culture. It can be argued that the gogy using such cultural markers to illustrate important scien-
works of Mary Shelley, Jules Verne, George MacDonald, and tific principles. If science education is attracting fewer students
Edgar Rice Burroughs, among others, laid the foundation for to graduate level study, constituent members of the American
the Golden Age of comics (1930s to the early 1950s), intro- Physiological Society should search for ways to popularize
ducing iconic characters whose stories continue to be retold in physiology. Perhaps exploring superhero physiology is a way
the cinema today. to reach people with the real thing. This is especially important
Inherent in these stories is the idea of the hero becoming now given the inordinate amount of time students spend
more than what he is. For example, in Tarzan of the Apes, consumed by popular culture (12). There is an opportunity here
Burroughs (5) creates a protagonist who has to overcome for science educators to connect with their students and turn
impossible odds to survive the nurturing of a female anthro- pop icons to their advantage by linking course content to a
poid. The boy adapts in body and mind to become perhaps the properly scientific exploration into the fantastic.
most enduring character of the 20th century. Sufficiently Building on the work of Zehr (36) and others (13), this paper
stressed by his feral existence, Tarzan is a perfect example of presents the physiology of physical performance by channeling
the innate adaptability of normal human biology, acquiring the creations of those whose imaginations gave us all of the
what we would consider superhuman abilities, yet of a purely great heroes of our youth. Our premise is that by connecting
natural origin. science to pop culture, students will learn to value the princi-
Genre novelists often employ strange or supranormal phys- ples of human physiology, taking their knowledge into places
ical/physiological capabilities gained through mysterious they would least expect to need it, for example, a superhero
means as major plot devices. For example, in Mary Shelley’s movie. As Zehr (36) puts it, “Superheroes can make great foils
classic work Frankenstein the antagonist uses arcane science to for exploring the limits of human biology and the impact of
create his monster. Ironically, the monster ends up being more technology on training and performance.”
human than his creator and, it can be argued, has achieved Recently, we challenged our graduate exercise physiology
students with this very principle via pointed questions posed
Address for reprint requests and other correspondence: S. P. Brown, Dept.
using such pop icons. Superhero physiology can help students
of Kinesiology, P. O. Box 6186, Mississippi State University, Mississippi grasp the normal adaptations biological systems undergo when
State, MS 39762 (e-mail: spb107@msstate.edu). repeatedly stressed. Our purpose in writing this article is
16 1043-4046/17 Copyright © 2017 The American Physiological Society
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 SUPERHERO PHYSIOLOGY 17

twofold: 1) to explore the physiological basis of Captain pathway of protein synthesis, which is important to facilitate
America’s physical capabilities as shown on film and 2) to skeletal muscle hypertrophy and increased strength (2).
show how educators can use the pop icon in their lectures to The complexity of the transcriptional factors affected by
help students better understand normal performance physiol- suppression of NCoR1 is significant since this intramuscular
ogy. injection could modulate several proteinaceous molecules in-
volved in muscular strength and endurance capacity adapta-
Super Soldier Serum: Mechanisms of Action
tions. To demonstrate the breadth of proteins involved in such
The 1940s story of a young man who did not meet physical adaptations, endurance training is typically associated with
screening criteria for entry into the US Army is inspiring to various transcription factors and coactivators such as the per-
many, including professionals in the field of exercise physiol- oxisome proliferator-activated receptor (PPAR) and receptor ␥
ogy. The Vita-Rays and intramuscular injection of the super coactivator 1␣ (PGC-1␣), the estrogen-related receptor (ERR),
soldier serum provided extensive physical and physiological cAMP response element binding protein (CREB), and the
changes, all of which are unachievable even with years of NAD⫹-dependent deacetylase sirtuin-1 (SIRT1) (6). These
intense exercise training. It is most plausible that the super signaling molecules are known to work to increase PGC-1␣
soldier serum precipitated genetic mutations and significant activity and allow for mitochondrial biogenesis, thus facilitat-
alterations in gene expression, affecting multiple protein path- ing aerobic adaptations to exercise training. However, some
ways involved in the promotion of skeletal muscle hypertrophy reports demonstrated that the activation of these proteins may
and improvements in structural and metabolic mechanisms of downregulate mTOR, which may have an adverse effect on
exercise endurance capacity and body composition. This paper skeletal muscle hypertrophy. This may occur via phosphory-
considers some of the physiological changes that may have lation of the mTOR inhibitor tuberin (tuberous sclerosis com-
occurred in Steve Rogers, a.k.a. Captain America, to permit plex 2) via AMP-activated protein kinase (AMPK) (2). Previous
such extraordinary performances while limiting fatigue and studies demonstrated that the suppression of NCoR1 may
overheating. These changes are displayed graphically in Fig. 1. facilitate increases in both aerobic capacity and muscular
One likely action of the super soldier serum was deactivation strength/hypertrophy (22, 34). Therefore, it is possible that the
of the muscle-specific nuclear receptor corepressor 1 (NCoR1) super soldier serum acted upon these pathways, especially
(34). To illustrate, trials utilizing knockout mice to examine the since these physiological adaptations are difficult to achieve
physiological effects of the suppression of this gene reported concurrently.
tremendous physiological enhancements, including increased Among Cap’s numerous likely genetic alterations are those
muscle mass and endurance, improved lipid oxidation, and affecting the MTSN and ACTN3 genes. The MTSN gene codes
skeletal muscle oxidative capacity (22, 34). These adaptations for myostatin [part of the transforming growth factor-␤
are extremely difficult to achieve through a single mode of (TGF-␤) superfamily], a group of proteins that regulates skel-
training, especially since endurance training has been shown to etal muscle growth and differentiation (21). Disruption of
deactivate the mammalian target of the rapamycin (mTOR) MTSN leads to myostatin-related muscle hypertrophy in sev-

Fig. 1. Summary of the likely physiological changes Steve Rogers endured to become a superhero. The iconographic star is a well-known symbol of Captain
America.

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18 SUPERHERO PHYSIOLOGY

eral species, most notably the Belgian Blue and Piedmontese The scientific explanation for this lies with metabolic effi-
cattle breeds and the Whippet dog breed (14). This has also ciency. The normal adult male or female is very inefficient, as
been demonstrated via a case study in humans (29). Problem- roughly 75– 80% of the energy liberated in the body during
atic are reports of reductions in myostatin, leading to increased metabolic processes is lost as heat (31). Thus, roughly 20 –25%
fatigability and reduced aerobic capacity (21). However, there of ingested calories are utilized for energy production. A case
is evidence to suggest that these decrements are not observed could be made that Captain America’s dietary demands are not
when knockout occurs postdevelopmentally (32). Additionally, different due to an improved metabolic efficiency. This is
it is likely that other genetic changes in Captain America, such supported by the fact that constant eating is not a part of his
as the suppression of NCoR1 described above, prevent these character as displayed in the movies. Nor do we see him
adverse consequences. sweating to dissipate the heat load associated with normal
Our second example is the ACTN3 mechanism of adaptation. physiological inefficiency. We propose three main adaptations
The ACTN3 gene codes for the ␣-actinin-3 protein, which is an to explain this: 1) a major improvement in digestive efficiency
actin-binding protein found on the Z-line that not only func- mediated through both greatly increased absorptive capacity
tions in cross-linking the actin filaments but also plays a and reduced dietary-induced thermogenesis (this aspect will
regulatory role in muscle contraction (35). Whereas several not be discussed further in this paper), 2) a greatly reduced
forms of ␣-actinin exist, the ACTN3 isoform has been found in metabolic energy expenditure in processes such as the Na⫹/K⫹
nearly all anaerobic athletes tested and has been termed the pump (discussed briefly below), and 3) tremendously enhanced
“sprinter gene” due to its extremely high prevalence in elite cellular substrate utilization (discussed in greater detail since
anaerobic athletes (35). It is likely that Steve Rogers possessed many physiological changes occur in response to chronic
ACTN3, as the ACTN3-deficient genotype is exhibited in only exercise training to allow for this effect).
18% of Europeans (35). Thus, we can see how these and other Captain America has a heightened metabolic efficiency
changes in gene expression profoundly influence physical per- through genetic mutations altering the ATPase family of pro-
formance via increased force production potential and im- teins. These include those of the Na⫹/K⫹ pump, sarcoplasmic
proved metabolic efficiency. reticulum Ca2⫹ transporter (SERCA pump), and others. En-
ergy expenditure through the Na⫹/K⫹ pump is responsible for
Metabolic Efficiency a significant portion of the energy demands of the resting body.
Referencing the scene mentioned earlier, Cap is shown to It is conceivable that genetic mutations generated a Na⫹/K⫹
perform a 13-mile training run in 30 min. Calculations using pump that has superior ion transport capacity per ATP utilized,
the American College of Sports Medicine (ACSM) equation to thereby greatly diminishing energy expenditure for the body
estimate V̇O2 during running (1a) yield a value of 142 and affording improved regulation of the membrane potential.
ml·kg⫺1·min⫺1. Estimating that his level of intensity during the Greatly attenuated energy expenditure in these and other areas
run was 80% of V̇O2max, his V̇O2max is predicted to be 177 would substantially reduce heat production, thereby allowing
ml·kg⫺1·min⫺1. This value far exceeds human capability, as more of Cap’s energy production to directly fuel muscle
only a small number of elite male endurance athletes have contraction.
recorded maximal values in the range of 94 to 96 ml·kg⫺1·min⫺1
(16). An increased metabolic efficiency could translate to Body Mass and Energy Storage
improved endurance capacity, decreased susceptibility to mus-
cular fatigue, and improved muscle force generation. Below, The body mass of Captain America is normal for a well-
we delve more directly into the role played by the cardiovas- muscled adult male of equal stature. Therefore, in terms of
cular system in giving Captain America such a heightened immediately available stored energy, it could be theorized that
aerobic power. Captain America has roughly 8 kcal of energy stored in the
Captain America is rarely seen ingesting food. This is form of ATP and 29 kcal of available energy stored as
significant since energy substrate utilization depends on caloric phosphocreatine (PCr). These phosphates contribute to events
consumption. This is also directly relevant to statements made that demand an immediate or rapid source of energy (31). For
in the movies that Captain America has a resting metabolic rate a person of his mass, Captain America likely stores roughly
four times above the normal human, making him resistant to 2,900 kcal as carbohydrates, with the overwhelming majority
the effects of alcohol (shown in Captain America: The First (~2,200 kcal) stored in lean tissue (i.e., skeletal muscle). The
Avenger). The normal resting rate of oxygen consumption is remaining 670 kcal is found in the liver (560 kcal stored as
3.5 ml·kg⫺1·min⫺1 (15). Four times this value places Captain glycogen) and serum (112 kcal as circulating glucose) (19).
America’s resting metabolic rate at 14 ml·kg⫺1·min⫺1. With a His muscle characteristics (mainly improved mitochondrial
body mass of 109 kg and an estimated body fat percentage of capacity and greater aerobic enzyme concentrations) allow for
10%, this means that his resting caloric expenditure is 7.63 considerably enhanced capacity for aerobic oxidation of this
kcal/min, contrasted to a normal human of the same body mass substrate. Aerobic oxidation of carbohydrate is paramount
who expends roughly 1.9 kcal/min at rest. Hence, the elevated since the breakdown of glucose or glycogen via substrate level
resting metabolic rate tremendously increases Cap’s caloric phosphorylation in glycolysis allows for the generation of 2 or
demand to maintain body weight. However, that Captain 3 ATP, which is not sufficient to allow Captain America to
America is not shown constantly eating to meet this elevated achieve superhuman performance. Aerobic oxidation of these
resting caloric demand indicates that he does not need to ingest substrates allows for the generation of 32 or 33 ATP (~233
four times the amount of calories as would a normal 109-kg kcal/mol of glucose), which is in high demand to support the
adult male with a greatly exaggerated resting metabolic rate. rate of energy demand by his skeletal muscles.

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 SUPERHERO PHYSIOLOGY 19

Furthermore, enzyme activity is enhanced, allowing for (either a punch or kick) and send them airborne. Superhuman
extremely rapid ATP generation via aerobic oxidation. One of muscle capabilities are displayed throughout these movies. In
the greatest benefits of anaerobic oxidation of carbohydrates is Captain America: The First Avenger, Steve Rogers is in basic
the rapidity by which ATP can be generated. However, it is training and unable to keep up with other recruits while
likely that Captain America’s enzyme activity is enhanced by running. He lacks the strength to pull himself up a cargo net
specific changes allowing for extremely rapid progression of and is unable to do a proper pushup. In the super soldier
the oxidative pathways. Thus, ATP is generated at a much experiment, he instantaneously gains ⬎100 lbs. and grows ⬎1
more rapid rate. ft. in stature. In the ensuing action sequence, he easily leaps a
Although it may not be apparent, Captain America does fence that is ⱖ7 ft. tall. This type of superhuman power
have a significant amount of energy stored as fat (roughly generation is shown repeatedly, demonstrating that the changes
100,000 kcal) that can potentially be used for energy. Ninety- to his physiology are not solely metabolic.
three percent of this energy is found in adipose tissue, with 2% Captain America exhibits a power-producing potential much
found in muscle and the remaining found in plasma as triglyc- greater than Olympic level track and field athletes. Skeletal
erides or free fatty acids (19). We estimate between 30,000 and muscle ratios vary across all track and field events, with
50,000 kcal of energy is available in the form of protein. endurance athletes having a greater percentage of type I fibers
However, he probably has a reduced reliance on the utilization and sprint athletes and jumpers generally possessing greater
of amino acids for energy since he is much more efficient at percentages of type IIx fibers. To allow the power outputs we
utilizing fats and carbohydrates. see Captain America demonstrate, it is fair to speculate that his
In terms of the energy available in glucose, roughly 453
fibers possess the characteristics of fast twitch (type IIx) fibers,
kcal/mol remain unliberated through oxidative metabolism. In
yet his resistance to fatigue suggests that his muscle fibers also
addition to a greatly increased oxidative capacity, we propose
possess the characteristics of slow twitch (type I) fibers.
that Captain America also possesses novel pathways through
which he can unleash most of the chemical bond energy in Some of the special fiber characteristics that could account
carbohydrates and fats unavailable in normal humans. We for the high-force generation capacity found in type IIx fibers
theorize this adaptation because Captain America needs much are the myosin heavy chain (MHC) type and ATPase activity.
larger energy availability to perform his superhuman feats. He Muscle fiber characteristics are further elucidated in Table 1.
is apparently able to do so without consuming greater quanti- However, it is not always possible to make such a clear
ties of food. distinction in terms of muscle fiber type. The majority of his
To allow for Captain America’s improved ability to oxidize skeletal muscle fibers are likely a hybrid between type IIa and
carbohydrates and lipids, mitochondrial changes are impera- IIx fibers, hence his ability to sustain high-force production
tive. Suppression of NCoR1 allows for significant aerobic while being highly resistant to fatigue. These fibers have mixed
adaptations (22, 34), which are facilitated mainly by various concentrations of MHC isoforms that allow for the perfor-
protein complexes. These complexes include CREB and mance effects noted in Table 1.
SIRT1, which facilitate the activation of PGC-1␣ (6). This The combination of these characteristics is not dissimilar to
pathway is normally activated by the changes in cellular what is noted in type IIa fibers. Type IIa fibers have contraction
AMP/ATP ratios seen during intense energy deficit or a high velocities similar to those seen in type IIx fibers but also much
cellular demand for ATP (i.e., high intensity exercise). The of the fatigue resistance of type I fibers. It could be hypothe-
removal of NCoR1 activity results in significant activation of sized that much of his musculature is functionally similar to
PGC-1␣, which is independent of physical conditioning and normal type IIa fibers. However, this cannot be his sole muscle
can account for increases in aerobic capacity via mitochondrial fiber type. Captain America needs muscle characteristics not
biogenesis (22). However, this is likely only one mechanism of only to facilitate muscle action during fights and superhuman
action of the super soldier serum, since the cellular changes feats but also during the execution of activities of daily living.
that occurred in him are likely unachievable with only sup- Activities of daily living rarely require large-force production
pression of NCoR1. or rapid movements similar to what we would expect from type
IIa and type IIx fibers. Thus, at least a small percentage of his
Skeletal Muscle muscle fiber type must still consist of type I fibers.
Captain America’s muscle cells likely contain a much higher
mitochondrial density in contrast to normal humans. Given the Table 1. Characteristics of representative muscle types
extremely high oxidative capacity of his skeletal muscles, it is
likely that he has either a very high or nonexistent lactate Characteristic Type 1 Type 2A Type 2X
threshold (LT). Chronic exercise training leads to an increase Performance effect
in LT, which is attributed largely to an improvement in the Force production potential Low Moderate-high High
oxidative capacity of muscle fibers. Hence, Cap has a very high Fatigue resistance (endurance
ability to directly and indirectly oxidize lactate via lactate potential) High Moderate Low
shuttling (4) and stimulate the production of glucose from Contractile speed Low Fast High
Cellular characteristic (mechanism)
lactate via the hepatic Cori cycle. Glycolytic enzyme activity Low-moderate Moderate-high High
The other major changes noted with Captain America are ATPase activity Low Moderate High
increases in muscle endurance, muscle strength, and muscle Myoglobin concentration High Moderate-high Low
power. Cap is able to exert a tremendous amount of muscular Mitochondrial enzyme activity High Highest Low
Capillary density High Moderate Low
force, demonstrated by his ability to strike another individual

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20 SUPERHERO PHYSIOLOGY

Fatigue anaerobic energy production (27), 2) H⫹ being a competitive

inhibitor of the Ca2⫹-binding site on troponin C, thereby
A common utterance by Steve Rogers throughout his ap- reducing available active sites on actin (11, 27), 3) reduction in
pearances in Marvel movies is “I can do this all day.” Fatigue Ca2⫹ release from the sarcoplasmic reticulum (SR), possibly
is often described as the inability to maintain desired force or by reducing the opening of the ryanodine receptors on the SR
power output during repeated muscle contractions, and its
that release Ca2⫹ (33), and 4) promoting the reverse rate
causes have been the subject of much study and debate.
constant between the weakly and strongly bound states of the
Potentially, any decrement in any one part of the chain of
actomyosin complex in the cross-bridge cycle (11).
events that occurs from muscle stimulation to movement exe-
How does Cap control his acid-base balance? He may
cution may be a source of fatigue. Thus, the causes of fatigue
are multifactorial. Fatigue theories revolve around central and experience little rise in H⫹ because most of what is produced
peripheral sources, with central fatigue referring to causes is taken up by the mitochondria for use in the electron transport
originating in the central nervous system (CNS), whereas chain (ETC). Cap likely possesses a greater chemical buffering
peripheral fatigue originates outside the CNS. potential similar to that derived from training. He may also
Ironically, the first instance of the phrase “I can do this all have improved lung capacity and mechanics for improving his
day” occurs in Captain America: The First Avenger as Steve ventilatory buffering capabilities.
Rogers is being pummeled in an alleyway while still the
quintessential 90-lb. weakling. When motivational and arousal Accumulation of Pi
factors are changed, fatigue can be altered. During fatiguing
Accumulation of Pi in muscle is increasingly implicated as a
contractions, decreased activity of spinal motor neurons is
cause of fatigue, whereas the importance of accumulated H⫹
observed and thought to be caused by both decreased neural
drive from higher brain centers and peripheral feedback (27). has been increasingly challenged (33). Intracellular [Pi] nor-
Apparently, Steve Rogers possesses a high level of psycholog- mally rises from a resting value of 5 to ~30 mmol in heavy
ical drive from higher brain centers to “will” himself to endure fatigue (1). Captain America’s experiences a negligible rise in
through painful circumstances. However, in this first instance [Pi] during most types of exercise because of his huge aerobic
of the phrase, if not for the intervention of Steve’s best friend, capacity (Pi will be taken up by the mitochondria for use in
Bucky Barnes, the mousy Steve Rogers would have suc- oxidative phosphorylation). Only in extremely intense events
cumbed eventually due to physical/physiological limitations. would Captain America exceed his aerobic capacity to the
A central fatigue factor that has received much attention point that significant amounts of Pi would accumulate. Addi-
recently is the ratio of serotonin to dopamine. A rise in this tionally, he would recover more quickly than the normal
ratio contributes to tiredness and fatigue, whereas a reduced individual during these short bursts of very intense activities
ratio appears to cause arousal and improve performance (20). because his high aerobic capacity would quickly replenish his
Neurochemical changes may have imparted to Cap an optimum PCr stores and clear the Pi. The following briefly describes and
ratio, allowing for a mechanism that would help stave off provides support for a couple of the mechanisms through
central fatigue. which accumulation of Pi is thought to contribute to the power
Central fatigue factors are thought to be minor contributors decline in fatiguing exercise. Several other mechanisms exist
to fatigue when compared with peripheral factors (10). There beyond those detailed below.
are many potential sites to consider when examining peripheral Pi interferes with force production through multiple means,
fatigue. These include events originating in the excitation- including direct interference with the cross-bridge and decreas-
contraction coupling process, at the cross-bridge, and/or in the ing Ca2⫹ release from the SR. Pi is theorized to enter the SR
metabolic pathways (10). The type of exercise dictates the through a phosphate-permeable channel discovered by Laver et
nature of the peripheral fatiguing factor. These may include al. (17), where it forms a Ca2⫹Pi precipitate. The Ca2⫹Pi
dehydration, hyperthermia, glycogen depletion, declining blood precipitate causes a decline in Ca2⫹ release from the SR,
glucose levels, posttranslational changes in proteins, and the reducing the number of available actin active sites capable of
accumulation of metabolic products. Metabolites suggested to forming cross-bridges due to steric blocking of actin active
have varying roles in fatigue include ADP, PCr, Mg2⫹, H⫹, sites by tropomyosin, when Ca2⫹ is not bound to troponin C.
K⫹, lactate, inorganic phosphate (Pi), and reactive oxygen and This mechanism is supported in the literature (7, 8, 26).
nitrogen species (1). Although Captain America likely dis- Both H⫹ and Pi are thought to directly interfere with the
played better control of most, if not all, of the preceding factors cross-bridge through a reduction in the number of cross-
listed, for illustrative purposes this discussion is limited largely bridges and/or the amount of force produced per cross-bridge.
to two key factors paramount to Captain America’s great Upon initial actomyosin complex formation, a weak bond state
endurance: better regulation of acid-base balance and lack of a is formed, which then transitions to more strongly bound
significant rise in Pi. high-force states. It seems that both of these metabolites favor
the reverse rate constant between the weakly and strongly
Regulation of Acid-Base Balance
bound cross-bridge states. This certainly would make sense for
Acid-base balance must be tightly controlled. Historically, Pi, as it is normally released from the actomyosin complex in
acidosis occurring during exercise was implicated as a major the transition from the weakly to strongly bound state. There-
cause of fatigue, although recent evidence calls this into fore, an increase in Pi would tend to drive the reaction toward
question (33). The mechanisms of action by which the accu- the weakly bound state. Likely, H⫹ accumulation more greatly
mulation of H⫹ (low pH) is thought to cause fatigue include stimulates the reverse reaction by changing reaction kinetics.
the following: 1) reduced activity of enzymes of aerobic and Support for Pi and H⫹ acting through separate mechanisms

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 SUPERHERO PHYSIOLOGY 21

within the cross-bridge is given through research showing their (lower than usual ESV at maximal exercise) mechanisms.
effects to be additive (11). These factors working alone or in combination would maxi-
mize SV at a much higher level than normal human physiology
Cardiovascular System allows.
An enhanced sympathetic drive during maximal exercise
As previously noted, Captain America has a predicted would also aid Cap’s cardiac performance by producing a
V̇O2max of 177 ml·kg⫺1·min⫺1 (19,293 ml/min for a 109-kg higher maximal HR and an even lower ESV, the latter by a
person). This doubles the typical V̇O2max (usually in the 80s) of
greatly enhanced myocardial contractility. Myocardial contrac-
Boston Marathon winners who achieve this level through
tility can be viewed as the rate of change of the ventricular
rigorous physical training as an outgrowth of great genetic
pressure with respect to time (dP/dt). Captain America is able
propensity. High values for this key metabolic variable corre-
late quite well with endurance performance but usually do not to achieve a much higher than normal inotropic state, affecting
perfectly explain performance differences. In Captain Amer- cardiac performance independent of preload and afterload.
ica’s case, his aerobic power is similar to what the thorough- Potential mechanisms for this would be anything that enhances
bred horse and the racing greyhound can produce, with both of Ca2⫹ channel activity in myocardial cells. Also, similar to
these athletes often exceeding 200 ml·kg⫺1·min⫺1. But how is normal human endurance exercise adaptation, Cap could have
this possible for a human athlete? an enhanced ability to reduce his cardiac afterload via a larger
This paper is limited to cardiovascular changes only given than normal decrease in peripheral vascular resistance, which
that the upper range of normal pulmonary ventilation is not a plays a permissive role in increasing cardiac SV.
limiting factor in Cap’s elevated aerobic power. Thus, we Maximal Q̇ is also greatly influenced by maximal HR. If
believe the super soldier experiment did not result in substan- Captain America is 30 yr old (he actually is nearly 100 yr old,
tial alterations to normal ventilatory dynamics. This section, but that’s a different story for another paper), his hypothesized
therefore, explores only a small portion of the cardiovascular maximal HR would be 190 beats/min (220 – age). However,
possibilities for such a high aerobic power, with the determi- the relationship between age and maximal achievable HR is no
nants of V̇O2max discussed via the Fick equation [V̇O2max ⫽ longer valid for him. So then, to achieve superhuman values for
Q̇max (CaO2 ⫺ Cv៮O2)max]. The Fick equation can be rewritten Q̇ and in keeping with the thoroughbred comparison, we can
as follows: V̇O2max ⫽ HR (EDV ⫺ ESV) ⫻ (1.34 ⫻ [Hb] ⫻ say that Cap’s maximum rate of cardiac depolarizations is
SaO2) – (1.34 ⫻ [Hb] ⫻ Sv៮O2), where EDV is the end- closer to 250 beats/min. This is the approximate upper limit for
diastolic volume and ESV is the end-systolic volume. Inherent thoroughbred race horses (24).
in Fick’s formulation is a central delivery component: the At this point, we can speculate on Cap’s maximal Q̇ as a
volume of blood sent to the working muscles [HR (EDV ⫺ function of HR and SV: Q̇ ⫽ HR ⫻ SV (Q̇ ⫽ 250 beats/min ⫻
ESV)], representing the maximal outflow from the heart 300 ml/beat ⫽ 75,000 ml/min or 75 l/min). The prediction of a
(Q̇max). The peripheral component, (1.34 ⫻ [Hb] ⫻ SaO2) – SV of 300 ml/beat is made on the basis of Cap’s hypothesized
(1.34 ⫻ [Hb] ⫻ Sv៮O2), represents the maximum amount of relative heart mass of 1.5% of his body mass (109 kg), putting
oxygen extracted by the working muscles. his heart mass at 1.6 kg. The 300 ml/beat value is proportional
The value of each of the variables in the equation can be to that of a thoroughbred horse (i.e., 1,400 ml/beat at a heart
manipulated in such a way as to arrive at Cap’s high V̇O2max. mass of 7.5 kg) as we continue the interspecies comparison
Reading the equation from left to right, the first step is to representative of how Cap’s heart structure and function
consider the heart. A high cardiac output is aided by a high
changed during the experiment (25). This heart size is much
ratio of heart weight to body weight (g/kg). For elite normal
larger than normally functioning human hearts and is even
humans, this ratio approaches 1% (~0.8%), with untrained
larger than hearts subjected to years of pathological load
humans mostly falling in the 0.4% range. However, the relative
weight of thoroughbred horse hearts averages ~1.5% (25). We stresses, i.e., chronic volume or pressure overloaded condi-
can hypothesize that with gains in overall body size during the tions. Like the well-trained human athlete, however, Cap’s
super soldier experiment, Captain America’s heart grew at a cardiac hypertrophy is not accompanied by decrements in
disproportional rate, placing his ratio closer to that of species myocardial performance. Thus, in combination with a larger
with far greater aerobic power than the best human athletes can than normal blood volume, heart mass, ventricular chamber
achieve. The increased heart mass comes with a commensurate diameter, and probable greater contractile state at maximal
increase in left ventricular chamber diameter, the ultimate exercise, Captain America produces a much larger than normal
effect being much greater EDV, stroke volume (SV), and maximal SV.
resultant cardiac output. Elite male distance runners have been shown to generate
Assuming that his blood volume changed proportionally to maximal SVs in the range of 187 ml/beat (37). The size of
his body mass, he has ~6.6 liters of blood, the predicted value Cap’s maximal SV is 60% greater than what normal elite
for a 240-lb. man. For Captain America, this value may be distance runners typically produce. Together with Cap’s ele-
higher given that one goal of the super soldier experiment was vated maximal HR, the large SV accounts for his (maximal) Q̇
to endow the subject with a large aerobic power. Cardiac being 114% larger than normal for the athlete with a maximal
performance is governed by three mechanisms: preload, after- Q̇ approaching ~35 l/min (37). The Q̇ value now determined,
load, and inotropic (contractile) state. A greater blood volume we can derive the peripheral factor (CaO2 – Cv ៮O2) given in the
accommodated by a larger heart would lead to a much larger Fick equation:
maximal SV (SV ⫽ EDV ⫺ ESV) due to enhanced Frank-
Starling (preload, i.e., increases in EDV) and contractility 19,293 ml O2 ⁄ min ⫽ 75,000 ml bl ⁄ min (CaO2 – Cv៮O2)

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22 SUPERHERO PHYSIOLOGY

Solving the equation yields a value for CaO2 – Cv ៮O2 of information can be used in the classroom. The key here is to use
0.257 ml O2/ml bl (~26 vol%), ~63% larger than the maximum the pop icon as a fun way to encourage critical thinking and spark
value (~16 vol%) reached by top human athletes (37). in-class discussions. The Socratic Method is perfect for leading
The variables of Fick’s equation can be manipulated in students in the analysis of key concepts and ideas to help them
several ways to yield Cap’s predicted V̇ O 2max of 177 question assumptions being made and to explore the implications
ml·kg⫺1·min⫺1 (19,293 ml O2/min). One way to derive such and consequences of those assumptions.
a high aerobic power is to alter the equation’s parameters so In-class discussions regarding superhero physiology are en-
that such a drastic increase in heart size is not necessary. To couraged, as is the use of essay questions during testing.
accomplish this, consider more closely the peripheral ex- Additionally, questions involving calculations related to me-
traction portion of the equation. tabolism and aerobic capacity could be posed as a group
In some species, the spleen acts as a reservoir for eryth- assignment, an individual assignment, or part of a test. As long
rocytes, which can be tapped into when the animal is under as the student is given the necessary parameters to use and a set
duress, as in exercise (9). Blood cells stored in the spleen of suppositions to make, they can derive concrete answers
can be mobilized into the circulation when there is an similar to that which is presented in the bioenergetics and
increased demand. When the plasma volume remains essen- cardiovascular portions of this paper. Multiple approaches can
tially unchanged or when there is a reduced plasma volume, be employed in teaching physiology using a superhuman spec-
the result will be an increase in hematocrit of ~30% in the imen like Captain America. Applications may be made repeat-
thoroughbred, with a concomitant increase in blood viscos- edly throughout the term with each new topic addressed. Or, at
ity (25). Interestingly, the increase in viscous resistance is the end of the term, the instructor could dedicate one or more
not enough to impede Q̇. class periods to the pop icon in question. Another possibility is
Therefore, we can hypothesize a similar mechanism for to design a class project (either individually or in groups)
Captain America thanks to the super soldier serum and the centered on the icon. Other superheroes could also be used,
use of genetic manipulation, giving Cap this same splenic comparing one superhero with the next and discussing the
reserve. During exercise, then, Cap calls on his erythrocyte physiological reasons why one hero would beat another if they
reserve, which would allow him to increase Hb concentra- were to fight. Ultimately, we believe the use of superhero
tion from 15 (at rest) to 24 g/dl (roughly the same as a physiology in the classroom is limited only by one’s imagina-
thoroughbred would produce during exercise). This in- tion as a teacher.
creased amount of Hb elevates the amount of O2 that can be Proposed questions are as follows:
delivered to the tissues (18). 1. Discuss the modulations in protein pathways that likely
How does this play out in the Fick equation? Provided Cap’s occurred to allow Cap to perform his superhuman feats.
Hb molecule remained normal after the experiment, 1 g of Hb 2. Discuss genetic mutations that likely occurred in Cap.
still binds ~1.34 ml O2. If during exercise his Hb concentration 3. Physiologically, how is Cap able to have a metabolic rate
reaches 24 g/dl, this would give him an oxygen carrying four times that of a normal human that does not neces-
capacity (CaO2) of 31.2 ml O2/dl [(24 ⫻ 1.34 ⫻ 0.97) ⫹ 0.03], sitate increased food consumption?
a 48% increase at 97% saturation using a reference value of 4. Propose a likely muscle fiber type profile for Cap and
21.1 ml O2/dl. The 0.03 in the previous workup represents the defend your hypothesis.
amount of oxygen dissolved in physical solution. Therefore, 5. Considering the physiological changes induced by the
based on a value of 31 ml O2/dl for CaO2 and ~24 ml O2/dl for super soldier serum, explain how these factors can allow
the arteriovenous oxygen difference, the Cv៮O2would be 7 ml for reductions in exercise-induced acidosis and/or fa-
O2/dl. If Cap’s Cv៮O2 was even lower, his maximal arterio- tigue.
venous oxygen difference would be even higher, thus reducing 6. Regarding Cap’s physiological/metabolic alterations, dis-
the need for the central circulation [Q̇ ⫽ HR (EDV ⫺ ESV)] to cuss which of these (if any) are realistic in terms of
play such a large role in his maximal aerobic power. potential occurrence in humans, and if so, to what extent.
Also, it is known that O2 transport capacity is correlated 7. Using Cap’s training run on The Mall in Washington, DC
directly with aerobic performance, as can be seen from an (shown in Winter Soldier), discuss estimations of the
increase in performance after infusion of red blood cells (3). expected V̇O2max of Captain America.
There is also a strong correlation between total Hb and V̇O2max 8. Discuss the physiological adaptations necessary for Cap
in athletes (28). Given that Captain America can deliver much to run 13 miles in 30 min.
more O2 than normal to the working muscles due to central 9. Considering the changes brought about in Cap’s car-
cardiac and hematological changes, it also makes sense that he diovascular system via the super soldier experiment,
would have the ability to extract more O2. Extra extraction address the following: 1) find alternate ways in which
would be dependent on the microvasculature in the working Cap could achieve a maximum aerobic power of 177
muscle and an increased mitochondrial density with the com- ml·kg⫺1·min⫺1 and 2) compare and contrast exercise
mensurate aerobic enzymatic machinery necessary to facilitate performance capabilities between different species and
such a high aerobic power and eventual ATP production. superheroes like Captain America.

Pedagogical Applications Conclusion

We have explored some of the physiological changes that could To treat our hypothesis adequately, this article has necessar-
have occurred in Captain America to explain the feats he performs ily dealt exclusively with Captain America. We also chose to
in Marvel movies. We now turn our attention to ways this focus this discussion on his movie exploits, which compel-

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 SUPERHERO PHYSIOLOGY 23

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ology student at Mississippi State University) for her artistic contributions in 22. Pérez-Schindler J, Summermatter S, Salatino S, Zorzato F, Beer M,
the creation of the images in this paper. Balwierz PJ, van Nimwegen E, Feige JN, Auwerx J, Handschin C. The
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DISCLOSURES in the regulation of skeletal muscle function and oxidative metabolism.
Mol Cell Biol 32: 4913– 4924, 2012. doi:10.1128/MCB.00877-12.
No conflicts of interest, financial or otherwise, are declared by the authors.
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dogs. Compr Physiol 1: 1–37, 2011. doi:10.1002/cphy.c091001.
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S.P.B. prepared figures; S.P.B., J.S., M.M., and L.J. drafted manuscript; Dukes’ Physiology of Domestic Animals (13th ed.) (edited by Reece WO).
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