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ENERGY CONVERSION IN SKELETAL MUSCLES: 
OLD AND RECENT VIEWS
Carlo REGGIANI
University of Padova, Department of Anatomy and Physiology, Via Marzolo 3, 35131 
Padova, Italy
e-mail: carlo.reggiani@unipd.it
ABSTRACT
The basic principle of the approach to human physiology used by Santorio Santorio 
was the conservation of mass: perspiratio insensibilis allowed a perfect balance be-
tween input and output: si cibus et potus unius diei sit ponderis octo librarum, transpi-
ratio insensibilis ascendere solet ad quinque libras circiter. Muscle contractile activity 
(corporis motus violentus), however, disturbs the balance between visible and invis-
ible evacuations. At the time of Santorio, the pneuma hypothesis of muscle contraction 
was still generally accepted and a long series of studies were necessary before the 
energy conservation principle could be applied to muscle contraction. The idea that 
in accordance with the energy conservation principle, chemical energy is transformed 
into work (mechanical energy) and heat (thermal energy) during muscle contraction 
was accepted only in the first half of the nineteenth century. It took approximately one 
hundred years before ATP was identified as the unique source of chemical energy for 
muscle contraction and the different ATP regeneration pathways were discovered. To-
day a wealth of tools is available to study the energy conversion in muscle contraction 
in single muscle fibres in vitro as well as in muscle in situ or in the whole organism 
during exercise. Myosin has been identified as the molecular motor performing the 
chemo-mechanical energy conversion and a number of specialized variants of myosin, 
employed for postural tasks or for power generation, have been discovered and anal-
ysed in detail.
Keywords: muscle energetics, thermodynamics, biochemistry, physical activity
review article                    UDC: 612.7:577.31
received: 2011-07-30
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PRETVORBA ENERGIJE V SKELETNIH MIŠICAH: STARI IN NOVI POGLEDI
IZVLEČEK
 
Ohranitev mase je bilo osnovno načelo, s pomočjo katerega je Santorio Santorio 
pristopal k obravnavi fiziologije človeka: perspiratio insensibilis je omogočalo popolno 
ravnovesje med vnosom/vhodom in iznosom/izhodom: si cibus et potus unius diei sit 
ponderis octo librarum, transpiratio insensibilis ascendere solet ad quinque libras cir-
citer. Za mišično aktivnost oz. krčenje (corporis motus violentus) pa je bilo tako rekoč 
mišljeno, da moti ravnovesje med vidno in nevidno evakuacijo. Dihanje mišic med nji-
hovim krčenjem je bila v Santorievem času še vedno splošno sprejeta domneva in bilo 
je potrebnih še veliko število študij, preden se je načelo ohranitve energije preneslo tudi 
na mišično krčenje. Ideja, da se kemična energija med mišičnim krčenjem pretvori v 
delo (mehansko energijo) in toploto (toplotno energijo) po načelu ohranitve energije, je 
bila sprejeta šele v prvi polovici 19. stoletja. Vendar pa je bilo potrebnih približno sto 
let, preden se je ugotovilo, da je ATP edini/edinstveni vir kemične energije, ki omogoča 
mišično krčenje, ter odkrilo različne poti obnove ATP. Danes je na voljo cela vrsta 
orodij oz. instrumentov, s pomočjo katerih lahko preučujemo pretvarjanje energije med 
mišičnim krčenjem, tako na nivoju posameznih mišičnih vlaken in vitro kakor tudi na 
ravni mišice in situ ali pa na ravni celotnega organizma med gibanjem/vadbo. Za mi-
ozinske niti je bilo ugotovljeno, da so molekularni motor, ki opravlja kemo-mehansko 
pretvorbo energije. Odkrite in podrobno preučene pa so bile tudi številne posebne/
specializirane različice miozina, ki se vključujejo v naloge ohranjanja ravnotežja ali 
kadar so potrebe po generiranju moči/silovitosti velike. 
 
Ključne besede: energetika mišic, termodinamika, biokemija, telesna aktivnost
Santorius and the old views on muscle energetics
The present view on skeletal muscle energetics is the end point of a long path which 
started centuries ago. Along this path, the work of Santorius marked one of the first 
steps with two extremely important contributions: the first contribution was the care-
ful application of a quantitative approach in the study of biological processes, while 
the second contribution was the proposal of a mass balance in the human body – or 
in other words, of a mass conservation principle. The amount of food and drink must 
precisely correspond to the amount of weight loss measured on a balance “stadera or 
weighing chair” made to the appropriate size for the human body. While the amount of 
food and drink could be precisely weighed, the weight loss could be divided into frac-
tions:  the amount lost in measurable excretions (urine, perspiration, faeces …) and 
the amount of weight lost in a form not measurable was referred to as “transpiratio 
insensibilis”. According to the fifth aphorism: “Insensible Perspiration is either made 
by the Pores of the Body, which is all over perspirable, and cover’d with a Skin like a 
Net; or it is performed by Respiration through the Mouth, which usually, in the Space 
of one Day, amounts to about the Quantity of half a Pound, as may plainly be made 
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appear by breathing upon a Glass”. Thus, a basic equation was proposed by Santorius 
in the sixth aphorism: “si cibus et potus unius diei sit ponderis octo librarum, transpi-
ratio insensibilis ascendere solet ad quinque libras circiter” i.e. every day 8 pounds of 
food and drink enter the body and 8 pounds leave the body: 5 as detectable or measur-
able excretion and 3 as undetectable excretion (transpiratio insensibilis). The lack of 
balance between the two components was considered to be either an indication of the 
existence of or the cause of pathological conditions (Santorius, 1614).
In the above depicted frame, muscle contractile activity was considered a possible 
cause of balance alterations and to some extent it was considered advisable to avoid any 
heavy physical activity motus violentus. The suggestion to keep physical activity within 
moderate limits was reminiscent of the view presented just some decades previously by 
Girolamo Mercuriale (1530–1606), who was also professor at the University of Padova 
(1575–1587) in his book De Arte Gymnastica (Mercuriale, 1569).
At the time of Santorius, there was no idea of a possible connection between energy 
derived from food intake and energy released during muscle contraction. The theory of 
muscle contraction widely accepted at the University of Padova by Vesalius and Harvey, 
not to mention Galileus, and shared by Santorius himself was based on the the hypoth-
esis that a biological fluid indicated as pneuma could reach the muscles running along 
the nerves, inflate the muscles and cause them to shorten. Such a theory did not give 
much consideration to the quantitative application of the mass conservation principle put 
forward by Santorius and was destined to be challenged over the subsequent decades. 
Swammerdam (1737) showed that muscle volume remains constant during a contrac-
tion, Stensen (1667) provided evidence in favour of fibre shortening as the first process 
in muscle contraction and a complete presentation of the iatromechanical approach to 
muscle function was reported by Borelli (1680) in his book De Motu Animalium. 
Historical development of muscle energetics
Scientific development in the 18th century brought two great advancements in the 
understanding of muscle contraction: the development of chemistry lead to the discov-
ery that oxygen is used for muscle contraction, thus chemical processes give power to 
muscles (Lavoisier, 1777). In parallel to this, the demonstration that electrical phenom-
ena take place in muscles established the basis for the foundation of electrophysiology 
(Galvani, 1791).
It was only around the first half of the 19th century that the principle of energy con-
versation came into consideration in muscle physiology in close relation to the devel-
opment of thermodynamics. This achievement can be ascribed to the German school 
of muscle physiology: mechanical recordings and heat production measurements were 
carried out during contraction and related to the catabolism of some not yet defined 
chemical compounds (Schwann, 1835; Helmoltz, 1847; Heidenhain, 1864)
In more recent years, the modern view of the energetics of muscle contraction 
emerged as the result of work carried out in the first half of the 20th century: Hill and his 
colleagues provided a complete analysis of the mechanical output and heat production 
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in muscle contraction (summarized by AV Hill in his book published in 1970), while 
Meyeroff and Lohmann (1930, 1931) studied the metabolic reactions which supply 
energy for muscle contraction and this lead to the discovery of ATP. In the emerging 
picture all chemical energy from energy substrates is spent to produce ATP, which is in 
balance with CP. ATP hydrolysis releases energy which is converted into work and heat.
Modern views of muscle energetics
According to the currently accepted view, the interaction between myosin and actin 
or the cross bridge cycle is the specific process that powers muscle contraction. After 
the action potential triggered by electrical stimulation or acetyl choline release at the 
neuromuscular junction, force and work are produced in the muscle as the result of 
the activity of many individual cross bridges, each of which is formed by the attach-
ment of a single myosin head to actin molecules on the thin filament. The acto-myosin 
interactions split ATP in a cyclical process, as a first approximation one molecule of 
ATP is split in each cycle of attachment and detachment (for a review on cross bridge 
mechanism, see Barclay et al., 2010). Thus, most of the ATP consumption associated 
with muscle contraction is accounted for by the interactions of myosin molecules on 
actin filaments which generate force and displacement, with a lower but not neglige-
able component related to ions pumping across membranes, in particular Na+ and K+ 
through the sarcolemma (Na/K pump) and Ca2+ through sarcoplasmic reticulum mem-
branes (SERCA pump). The ATP consumed for ion pumping is approximately 30–40% 
of the total ATP hydrolysed during contraction (for a review, see Barclay et al., 2007).
Force development in isometric contractions has a cost in ATP, a close proportion 
existing in number of ATP hydrolysed per second and the amount of force developed. 
When shortening occurs, ATP is further hydrolysed (Figure 1) and the degree of conver-
sion of the chemical energy released from ATP hydrolysis in mechanical work is quan-
tified by the efficiency. Efficiency can be determined at the level of the cross bridge 
cycle and at myofibrillar level and can reach values close to 50% (Smith et al., 2005). 
When the efficiency is determined during a contraction of an intact fibre, the fraction 
of ATP, and thus of energy, used for ionic pumps must be also considered. The value of 
efficiency in intact muscles or muscle fibres is therefore lower. Furthermore, efficiency 
can be also determined in muscles taking into account the regeneration process of ATP. 
Three distinct processes support ATP regeneration: CreatinPhosphate to ATP conver-
sion, anaerobic glycolysis and mitochondrial oxidative phosphorylation.
It is important to underline that distinct muscle fiber types have different energetic 
properties. The difference is very evident in the cost of tension generation (ATP per unit 
force per unit time) which is several times lower in slow compared to fast fibers (Stienen 
et al., 1996; He et al., 2000), see Figure 2. This makes slow fibres more convenient than 
fast fibres in being recruited for long lasting force generation tasks such as those related 
with posture. When external work is performed, efficiency is not very different between 
fast and slow fibres (Reggiani et al., 1997; He et al., 2000). This implies that the higher 
power developed by fast fibres can be exploited without energetic disadvantage.
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Figure 1: ATP consumption during contraction of a slow fibre of human muscle. Meas-
urements are carried out on a muscle fibre segment, dissected from a needle biopsy, 
permeabilized with Triton, activated with calcium at 20 °C. Contraction starts in an 
isometric condition and then shortening is allowed from sarcomere length of 2.7 μm to 
sarcomere length of 2.5 μm, as can be seen in the uppermost panel. Tension decreases 
during the shortening phase and reaches the level determined by the force-velocity re-
lation (see middle panel). ATP consumption is determined by the binding of inorganic 
phosphate to a fluorescent protein binding protein as described by He et al. (2000) and 
is shown in the lowest panel. Note the increase in ATP hydrolysis rate when shortening 
occurs and external work is performed, in comparison to the isometric condition.
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Santorius was deeply interested in developing equipment to measure physiological 
parameters. Nowadays, an unprecedented wealth of experimental tools enable muscle 
physiologists to quantitatively determine the energy conversion in vitro as well as in 
vivo, in single muscle fibers, in whole muscles or in the body. Specific methods allows 
the determination of the energy consumption rate in muscle fibers, ranging from experi-
ments on permeabilized fibers where the spectrophotometric determination of NADH 
oxidation (Stienen et al., 1996) or the use of a specific probe for inorganic phosphate 
permit to monitor the ATP hydrolysis (He et al., 2000), to microchemical determination 
of high energy phosphate in muscle biopsy samples (Karatzaferi et al., 2001), to enthalpy 
determination from heat and mechanical measurements (Barclay et al., 1993), to the mea-
surement of oxygen consumption (Homsher, 1987) and to 31P MR spectroscopy in vivo 
(Blei et al., 1993; Conley et al., 2000). Since all energy required for cellular functions, 
including contractile activity, is provided by ATP hydrolysis to ADP and Pi, the energy 
consumed by a muscle fiber can be measured in moles of ATP consumed as well as in 
Figure 2: ATP consumption (lower panels) and tension development (upper panels) 
during an isometric tetanus in a slow fibre (left) and in a fast fibre (right) from human 
vastus lateralis. Figure re-drawn and modified from Stienen et al. (1996). Fibre seg-
ments were dissected via a needle biopsy, permeabilized with Triton, activated with 
calcium at 20 °C. ATP consumption was determined from NADH oxidation in a spec-
trophotometer. NADH oxidation was enzymatically coupled with ATP hydrolysis in 1:1 
proportion as described in Stienen et al. (1996). Note the greater slope of ATP con-
sumption, i.e. the higher ATP consumption rate, in the fast compared to the slow fibre.
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energy units (calories or Joules) or in oxygen consumed for ATP regeneration in the mi-
tochondria, if contraction occurs in aerobic conditions.  It is generally accepted that the 
hydrolysis of 1 mole ATP releases between 50 and 60 kJ under physiological conditions. 
CONCLUSIONS
In conclusion, looking back over the four centuries which have passed since the 
time when Santorius was called to the chair of Medicina Teorica in Padua, we can 
recognize and identify the steps of the long path which lead from the mass balance prin-
ciple to the energy balance principle in muscles. The legacy of Sartorius is, however, 
still recognizable and can be well appreciated. We owe to him our quantitative approach 
in physiology: the passion for measuring all parameters in precise quantitative terms 
and designing the most appropriate tools necessary to meet this goal. We also owe to 
him the view that a balance must exist, the balance of mass and energy in the reactions 
which occur within the muscles and the body.
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