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Medical Hypotheses
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Blood ow restriction: The metabolite/volume threshold theory

J.P. Loenneke a,, C.A. Fahs a, J.M. Wilson b, M.G. Bemben a
a
b

Department of Health and Exercise Science, The University of Oklahoma, Norman, OK, USA
Department of Exercise Science and Sport Studies, University of Tampa, Tampa, FL, USA

a r t i c l e

i n f o

Article history:
Received 11 April 2011
Accepted 15 July 2011
Available online xxxx

a b s t r a c t
Traditionally it has been thought that muscle hypertrophy occurs primarily from an overload stimulus
produced by progressively increasing an external load using at least 70% of ones concentric one repetition maximum (1RM). Blood ow restricted exercise has been demonstrated to result in numerous positive training adaptions, specically muscle hypertrophy and strength at intensities much lower than this
recommendation. The mechanisms behind these adaptions are currently unknown but a commonly cited
concept is that acute elevations of systemic hormones, specically growth hormone (GH), play a large
role with resistance training induced muscle hypertrophy, possibly through stimulating muscle protein
synthesis (MPS). We hypothesize that the alterations in the intramuscular environment which results
in the rapid recruitment of FT bers, is the large driving force behind the skeletal muscle hypertrophy
seen with blood ow restriction, whereas the external load and systemic endogenous hormone elevations
may not be as important as once thought. It is further hypothesized that although skeletal muscle hypertrophy can be achieved at low intensities without blood ow restriction when taken to muscular failure,
the overall volume of work required is much greater than that needed with blood ow restriction.
2011 Elsevier Ltd. All rights reserved.

Introduction
Traditionally it has been thought that muscle hypertrophy occurs primarily from an overload stimulus produced by progressively increasing a mechanical load using at least 70% of ones
concentric one repetition maximum (1RM) [1]. As a muscle is overloaded from increased mechanical work, the added stress increases
amino acid transport into cells, which in turn enhances the synthesis of contractile proteins, actin and myosin. Muscle hypertrophy
occurs from both an increase in the thickness and in the number
of myobrils. Although hypertrophy occurs in both slow twitch
(ST) and fast twitch (FT) bers, the latter has a greater potential
for growth [2].
The American College of Sports Medicine (ACSM) recommends
lifting a weight of at least 70% 1RM to achieve muscular hypertrophy as it is believed that anything below this intensity rarely produces substantial muscle growth [1]. However, numerous studies
using resistance exercise training combined with blood ow
restriction have shown muscle hypertrophy to occur with a training intensity as low as 20% 1RM [37]. Blood ow restricted resistance training may induce hypertrophy through a variety of
mechanisms [8], with the most commonly cited mechanism being
a robust elevation in growth hormone (GH) levels [9]. It is accepted

Corresponding author. Address: 1401 Asp Avenue, Room 104, Norman, OK

73019-0615, USA. Tel.: +1 405 325 5211; fax: +1 405 325 0594.
E-mail address: jploenneke@ou.edu (J.P. Loenneke).

by many that acute elevations of systemic hormones, specically

GH, play a large role with resistance training induced muscle
hypertrophy, possibly through stimulating muscle protein synthesis (MPS) [10]. Recent studies suggest this mechanism does not
hold true with regular resistance training [11], further bringing
into question that specic mechanism with respect to blood ow
restricted exercise. The purpose of this paper will be to address
the following questions and help theorize the mechanisms involved with muscle hypertrophy from blood ow restricted
exercise:
(1) What role does intensity (%1RM) play with MPS and muscle
hypertrophy with blood ow restricted exercise?
(2) Is FT ber recruitment the most important factor for muscle
hypertrophy with blood ow restricted exercise?
(3) Do systemic elevations of endogenous hormones play a role
in MPS or muscle hypertrophy with blood ow restricted
exercise?

Exercise intensity
Exercise intensity, dened as a percentage of ones concentric
1RM, has long been used as a guide for muscle hypertrophy exercise prescription. Interestingly, if we accept that acute imbalances
between MPS and muscle protein breakdown (MPB) are the main
driving force of muscle hypertrophy, then exercise intensity may
actually be of less importance. Kumar et al. [12] found that the rate

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doi:10.1016/j.mehy.2011.07.029

Please cite this article in press as: Loenneke JP et al. Blood ow restriction: The metabolite/volume threshold theory. Med Hypotheses (2011), doi:10.1016/
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of myobril MPS was maximized at 60% 1RM, showing that the

rate of myobril MPS could be maximized at a lower intensity than
the ACSM recommendation of 70% 1RM. The non-signicant increase in myobril MPS with intensities between 20 and 40%
1RM, was likely due to the control of volume between groups,
meaning muscular failure was not reached in the lower intensity
groups. Burd et al. [13] showed that resistance exercise performed
at 30% 1RM to failure (4 sets) elevated myobril MPS to the same
level as 90% 1RM to failure (4 sets), demonstrating that perhaps
loading at an absolute intensity of 70% 1RM may not be necessary
to induce muscle hypertrophy. This is contrary to what has commonly been reported in the literature which states that training
to failure is not an effective stimulus without lifting at a sufcient
intensity dened by percentage of 1RM (80% 1RM), and it has always been thought that without blood ow restriction, high rep
training cannot produce a stress that is adequate to recruit and fatigue the highest threshold motor units [14].
Blood ow restricted exercise has been shown to elicit muscle
hypertrophy in numerous studies when combined with resistance
exercise performed well below the 70% 1RM recommendation [3
7] often using intensities between 20 and 30% 1RM. Mixed muscle MPS has been shown to be signicantly elevated following
acute blood ow restricted resistance exercise [15,16], further
building a case for the accretion of muscle mass independent of
external load. Although studies have not specically investigated
the myobril MPS response to blood ow restricted exercise, long
term training studies have indicated that the increases in muscle
hypertrophy are accompanied with a concomitant increase in
strength, indicating that the increases were functional in nature
[37]. In fact, Campos et al. [17] provides the only evidence that
exercise to muscle failure at higher intensities is more effective
than training at lower intensities for skeletal muscle hypertrophy
(4 sets 34 RM vs. 2 sets 2028 RM). Interestingly, Leger et al.
[18] using the identical methods outlined by Campos, observed
signicant increases in muscle hypertrophy, muscular strength,
and endurance independent of exercise intensity. It could be argued that the difference was due to the older less active subjects
used in latter study (36 vs. 22 years). The volume of exercise may
have been inadequate to recruit the higher threshold motor units
in the younger more active subjects used in the Campos et al. [17]
paper.
From the available evidence it appears that a training intensity
below the recommended 70% 1RM is capable of producing skeletal
muscle hypertrophy, particularly with the addition of blood ow
restriction. Hitherto the literature has argued that intensity is the
most important variable, and a load below 65% 1RM is insufcient
to promote muscle hypertrophy [19]. To say that the intensity from
an external load is the absolute deciding factor on muscle adaptation is inappropriate and Wernbom et al. [20] caution that estimating the stress imposed on each muscle ber merely by the
magnitude of the external load is too simplistic of an approach.
The intramuscular environment (i.e. metabolic stress) may play a
large role in the training adaptation. To illustrate, Goto et al. [21]
showed that two different exercise regimens at the same external
intensity (35 sets of 10 at 75% 1RM) resulted in different muscle
adaptations. The only difference between groups is that one group
rested for 30 s midway through each exercise set. The group that
did not rest midway through each set had greater increases in metabolic stress which resulted in greater gains in strength, endurance, and muscle mass compared to the group that rested during
each set. e isso interfere na hipertrofia?
We hypothesize that intensity determined by external load is
of less importance than changes in the intramuscular environment. Through the application of blood ow restriction, the intensity of exercise is able to be increased, without altering the
external load.

Fiber recruitment
Literature demonstrates similar MPS responses independent of
exercise intensity as determined by concentric %1RM [13,15,16].
MPS signaling from resistance training occurs primarily from the
activation of signaling proteins, primarily S6K1, which is approximately 3- to 4-fold higher in FT bers compared to ST (40). Phosphorylation of this signaling protein has shown to be predictive
of skeletal muscle hypertrophy (41). This supports FT ber recruitment being an important variable to consider when assessing potential for the accretion of muscle mass. Blood ow restricted
resistance exercise research has demonstrated that recruitment
of the higher threshold motor units (containing FT bers) does occur with lower intensity exercise. Investigations have shown increased integrated electromyography (iEMG) [5,9,22] and
inorganic phosphate splitting [23], likely from the reduction in
oxygen and subsequent metabolic accumulation, during blood ow
resistance restricted exercise. Both reduced oxygen and metabolic
accumulation can increase ber recruitment, mechanistically
speaking, through the stimulation of group III and IV afferents
which may cause inhibition of the alpha motorneuron, resulting
in an increased ber recruitment to maintain force and protect
against conduction failure [24].
Thus, muscle hypertrophy occurs independently of exercise
intensity, as long as FT bers are activated [25]. This may seem
to question the application of blood ow restriction training, if
similar results can be seen without restricting blood ow. However, such a low load exercise protocol without blood ow restriction would require signicantly more repetitions to be completed
in order to stimulate an increase in myobril MPS [2628]. Those
with lower limb injuries or the elderly may be incapable of sustaining the mechanical stress necessary to reach muscular failure. Thus
we hypothesize, based on current literature, that blood ow
restriction induces muscle failure earlier (i.e. -at a lower volume
of work) compared to non-restricted resistance exercise at the
same intensity [2628]. Based on this hypothesis, it appears that
resistance exercise protocols for blood ow restriction might maximize training adaption using sets to failure rather than the commonly used four set protocol which is 30 repetitions for the rst
set, followed by 3 sets of 15.

Endogenous systemic hormones

Elevated systemic hormones following acute resistance exercise
have long been associated with skeletal muscle hypertrophy with
and without blood ow restriction. However, Wilkinson et al.
[11] suggest that evidence supporting this relationship were typically found with retrospective correlations [2938]. Recent research is calling this association into question, with myobril
MPS and muscle hypertrophy occurring independent of exercise
induced endogenous systemic hormones (for a review please see
West and Phillips [39]).
Systemic elevations of endogenous hormones, specically GH,
do not appear to play a role in myobril MPS or muscle hypertrophy. To illustrate, Doessing et al. [40] found that 14 days of administering recombinant GH stimulated collagen synthesis but had no
effect on myobril MPS. Furthermore, Wilkinson et al. [11] found
signicant muscle hypertrophy of the knee extensors following
unilateral knee extension exercise at 8090% concentric 1RM,
without a systemic increase in GH.
Acute [41] and chronic [42] resistance exercise investigations
from West and co-workers further conrm the aforementioned
study. These studies investigated elbow exion with and without
the presence of signicant elevations of endogenous hormones
(GH, IGF-1, Testosterone). Acutely, resistance exercise resulted in

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j.mehy.2011.07.029

J.P. Loenneke et al. / Medical Hypotheses xxx (2011) xxxxxx

Fig. 1. The relationship between exercise volume, motor units recruited, and protein synthesis. As intensity increases from 3055% of ones repetition maximum the higher
threshold motor units are recruited. Once a certain amount of volume has been reached, as indicated by the threshold marker in the center of the gure, maximal protein
synthesis from exercise will occur. This occurs independent of exercise intensity provided the metabolic stress and/or volume is adequate to recruit the highest threshold
motor units.

signicant elevations in myobril MPS without an additional effect

from elevated systemic endogenous hormones [41]. To observe
long term exposure to exercise induced endogenous hormones,
West et al. [42] performed a 15 week resistance training study
using the same design, and conrmed that muscle hypertrophy increased with resistance training, without an additional effect from
the presence of elevated systemic endogenous hormones. In spite
of the current ndings, Schoenfeld [19] suggest that these studies
have experimental limitations and the dismissal of the larger body
of research supporting the association between systemic hormones
and muscle hypertrophy is without context and premature.
Although it appears that systemic elevations in anabolic hormones do not contribute to skeletal muscle hypertrophy, elevations
of localized hormones may. To illustrate, an animal model in which
the IGF-1Ea (systemic form) receptor was knocked out demonstrated that animals were still able to undergo muscle hypertrophy
[43]. One explanation might be due to the localized production IGF1Ec, better known as mechano growth factor (MGF). MGF is locally
increased in response to both mechanical stimuli and cellular damage, providing a potential mechanism for skeletal muscle hypertrophy [44]. However, Hornberger et al. [45] have observed increased
activation of the mammalian target of rapamycin (mTOR) pathway,
independent of locally activated growth factors, in response to
mechanical stimulation (passive stretch).
We hypothesize that an increase of systemic endogenous hormones above basal levels are unlikely to produce an increase in
muscle hypertrophy. Furthermore, we hypothesize that any hormonal involvement with muscular growth is instead related to
localized growth factors. Based on our hypotheses, we question
the commonly cited role of increased systemic endogenous hormones in the training adaptions observed with blood ow restriction. It is likely that these systemic elevations are more to do with
fuel mobilization and less to do with muscle growth.

Discussion
Current literature indicates muscle hypertrophy is largely
dependent upon elevated myobril MPS, which is independent of
external load as long as the volume and/or metabolic stress is sufcient to recruit FT bers (Fig. 1). Burd and co-workers have demonstrated that three sets of resistance exercise (70% 1RM)
performed to muscular failure produces a greater amplitude and
duration in MPS than one set of the same exercise to failure, highlighting the importance of resistance exercise volume [46].
Although we have long thought systemic increases of endogenous hormones play a role in myobril MPS and muscle hypertrophy, Wilkinson et al. [11] caution that those appear to only be
retrospective correlations. In addition, the role of muscle damage
in muscle hypertrophy may also be a spurious correlation, since
muscle hypertrophy occurs with blood ow restriction training
without elevations in known indices of muscle damage [9,47].
Muscle hypertrophy can occur through a variety of factors and
many of the mechanisms associated with growth are capable of
working independently of each other due to numerous redundancies built into the pathway (e.g. mTOR stimulation independent of
local growth factors) [48]. We hypothesize that the application of
blood ow restriction results in a rapid recruitment of FT ber
recruitment. Although, we do not believe that FT ber recruitment
is the single factor involved in the hypertrophic response to an
exercise stimulus, many of these other mechanisms (e.g. transcription factors, local growth factors, and satellite cells) likely occur in
concert with recruitment of higher threshold motor units observed
with blood ow restriction raining.
To illustrate, resistance exercise activates a signaling network
that regulates the expression of muscle growth factors such as
IGF-1, MGF, and myostatin. Local elevations in both IGF-1 and
MGF are positively associated with MPS [49] and both are impor-

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J.P. Loenneke et al. / Medical Hypotheses xxx (2011) xxxxxx

tant in satellite cell proliferation which is requisite for signicant

muscle hypertrophy with chronic training [50]. Myostatin, a negative growth factor, is inversely related with MPS and inhibits the
satellite cell cycle [51] but resistance exercise, even at low intensities has been shown to inhibit the expression of myostatin [52].
Muscle hypertrophy has been shown to occur through each one
of these factors independently. This does not mean that one is
more important than the other, but speaks to the complexity of
the overall network. It is our hypothesis that exercise of any intensity that requires the recruitment of FT bers would lead to the
hypertrophic signaling of this complex network and that when
completed under blood ow restriction, would result in muscle
hypertrophy at an overall lower volume of work than regular exercise to failure due to the local accumulation of metabolites in the
working muscle.
Future research could investigate these hypotheses, through a
long term training study using low intensity exercise to failure elucidating whether muscle hypertrophy occurs with low intensity
exercise induced elevations in MPS. In addition, with blood ow restricted resistance training, a low intensity group exercising to
muscular failure could be included in study designs to investigate
if muscle hypertrophy occurs at a level similar to the blood ow restricted group. This is important for blood ow restricted exercise
training, because research demonstrates that this mode of exercise
allows muscular failure to occur sooner and a control group exercising without the blood ow restriction, would be unlikely to recruit the FT bers needed for signaling MPS and subsequent muscle
hypertrophy if matched for work.
Perspectives
This paper focused on answering three specic questions with
respect to skeletal muscle hypertrophy and blood ow restriction.
The recruitment of FT bers appears to be the large driving force of
skeletal muscle hypertrophy whereas exercise intensities, based on
external load lifted, and systemic endogenous hormone elevations
may not be as important as once thought. Long-term training studies are clearly needed to verify that the elevations in myobril MPS
seen with low intensity exercise actually translate into skeletal
muscle hypertrophy.
Funding
This paper was not supported by funding from an outside
source.
Conict of interest statement
None declared.
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