Hackney et al.

Extreme Physiology & Medicine 2012, 1:12

http://www.extremephysiolmed.com/content/1/1/12

REVIEW

Open Access

Blood flow-restricted exercise in space

Kyle J Hackney1*, Meghan Everett2, Jessica M Scott3 and Lori Ploutz-Snyder3

Abstract
Prolonged exposure to microgravity results in chronic physiological adaptations including skeletal muscle atrophy,
cardiovascular deconditioning, and bone demineralization. To attenuate the negative consequences of
weightlessness during spaceflight missions, crewmembers perform moderate- to high-load resistance exercise in
conjunction with aerobic (cycle and treadmill) exercise. Recent evidence from ground-based studies suggests that
low-load blood flow-restricted (BFR) resistance exercise training can increase skeletal muscle size, strength, and
endurance when performed in a variety of ambulatory populations. This training methodology couples a
remarkably low exercise training load (approximately 20%50% one repetition maximum (1RM)) with an inflated
external cuff (width, ranging between approximately 3090 mm; pressure, ranging between approximately
100250 mmHg) that is placed around the exercising limb. BFR aerobic (walking and cycling) exercise training
methods have also recently emerged in an attempt to enhance cardiovascular endurance and functional task
performance while incorporating minimal exercise intensity. Although both forms of BFR exercise training have
direct implications for individuals with sarcopenia and dynapenia, the application of BFR exercise training during
exposure to microgravity to prevent deconditioning remains controversial. The aim of this review is to present an
overview of BFR exercise training and discuss the potential usefulness of this method as an adjunct exercise
countermeasure during prolonged spaceflight. The work will specifically emphasize ambulatory BFR exercise
training adaptations, mechanisms, and safety and will provide directions for future research.
Keywords: Blood flow-restricted exercise, KAATSU, Microgravity, Spaceflight, Bed rest, Unloading

Review
Introduction

Acute microgravity exposure results in rapid cephalad

fluid shifts, space motion sickness, vestibular impairment, and musculoskeletal unloading [1]. However, the
overall space environment encompasses both microgravity exposure and related challenges such as increased
background radiation, social isolation, disruption of circadian rhythm (sunrise every 90 min), and access to a
limited food variety (high salt prepackaged) and water
supply [1]. These environmental stimuli interact to elicit
chronic physiological adaptations including decreased
bone mineral content and density, compromised maximal
aerobic capacity, and reduced skeletal muscle mass and
strength [2]. The morphological and structural alterations
that occur within the skeletal muscle tissue as a result of
microgravity exposure were uncovered following several
* Correspondence: [email protected]

Equal contributors
1
Wyle Science, Technology and Engineering Group, Houston, TX 77002, USA
Full list of author information is available at the end of the article

Shuttle Transport System, Mir, and International Space

Station (ISS) investigations [3-5]. These data suggest that
the rate of skeletal muscle loss relative to the duration of
microgravity exposure is nonlinear, with the greatest losses
early in the mission. It is also evident that skeletal muscle
atrophy and dysfunction are most prominent in the knee
extensor (KE; 6% to 12%) and plantar flexor (PF; 6%
to 24%) muscle groups [6].
The physiological mechanisms of disuse- or unloadingrelated skeletal muscle atrophy have been previously
reviewed [7,8]. In brief, a change in skeletal muscle size is
a reflection of the temporal rates of muscle protein synthesis and degradation. For instance, across a 24-h period,
if the rate of muscle protein synthesis is greater than the
rate of breakdown, net muscle protein balance will be
positive and protein will be gained. In contrast, if the rate
of muscle protein breakdown is greater than the net rate
of muscle protein synthesis, the net balance will be negative and protein will be lost. Although debated, evidence
suggests that unloading induced skeletal muscle atrophy
in humans occurs primarily as a result of decreased basal

2012 Hackney et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

Hackney et al. Extreme Physiology & Medicine 2012, 1:12

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muscle protein synthesis and a reduced synthetic response

following feeding [7,9]. In-flight, variables such as participation in exercise countermeasures, age, gender, genetics,
stress level, total energy intake, macronutrient composition, and preflight fitness level can influence the rates of
muscle protein synthesis and breakdown; therefore, it is
difficult to systematically determine the most important
factor facilitating spaceflight-induced skeletal muscle atrophy, though the unloading itself is assumed to be the most
potent factor.
To defend against skeletal muscle atrophy and physiological deconditioning on the ISS, crewmembers perform
2.5 h per day (including time for equipment setup and
breakdown) of aerobic and/or resistance exercise; however, exercise prescription, exercise preference, and exercise adherence vary among crewmembers. The exercise
equipment on the ISS, including a treadmill, a cycle ergometer, and the Advanced Resistive Exercise Device
(ARED), have been engineered to operate in a weightless
environment and are housed within vibration isolation
systems to prevent damage to the ISS structure. During
treadmill exercise, crewmembers must wear special harnesses that attach to the sides of the treadmill via bungee cords to maintain contact with the treadmill surface
and to provide musculoskeletal loading during exercise.
Crewmembers adjust the length of the bungee cords to
set the pull-down load to a percentage (usually 60%
80%) of 1-G body mass. The cycle ergometer exercise
operates similarly to an upright/recumbent bicycle and
is used primarily for cardiovascular and aerobic conditioning. Resistance exercise in space is particularly challenging because the microgravity environment precludes
the use of traditional free weights or weight stacks.
However, ARED offers over 20 different resistance exercises including squat (SQT), heel raise, dead lift, bench
press, and upright row [10]. The resistance is provided
by vacuum cylinders that offer up to 273 kg of applied
external load [11], and inline flywheels simulate 1-G inertia when the load changes direction during exercise.
Since crewmembers are weightless in microgravity, the
large loading capability is required because body mass
must be added to the prescribed load in order to observe
similar musculoskeletal forces to those on the ground.
Thus, the current ISS exercise hardware allows for highintensity exercise, enabling crewmembers to run up to
12 mph on the treadmill and train with heavy loads
using ARED.
Although ARED and the other exercise devices provide excellent loading and resistance capabilities on the
ISS, this specialized exercise hardware is expensive to
build, launch, and maintain in an isolated spaceflight environment. Further, maintenance and repair must be
performed by crewmembers, and spare parts for the
complex devices may not be immediately available.

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Exercise hardware for future long-duration exploration

missions may need to be even more robust, compact,
and portable than the current devices. There may also
be fewer modes of exercise available to crewmembers,
and aerobic and resistance trainings may have to be performed on a single device. It is therefore important to
investigate adjunct therapies that might enhance the effectiveness of aerobic and/or resistance exercise in the
event that the exercise hardware itself poses limitations.
Exercising at a low intensity with blood flow restriction
(via inflation cuffs) has recently become a popular
method of training in Japan [12]. The purpose of this review is to present an overview of BFR exercise training
and discuss its potential usefulness as an adjunct exercise countermeasure for prolonged spaceflight.
BFR exercise prescription and training
BFR resistance training

BFR resistance exercise training (also known as

KAATSU when specific equipment is utilized [12]) combines low training intensity (approximately 20%50%
1RM) with an external pressure cuff applied to the exercising limb [13-16]. BFR exercise protocols vary and are
primarily influenced by cuff size, pressure, and the circumference (CIRC) of the limb being exercised [17];
however, most use three to five sets of exercise with 30to 90-s rest periods [18]. Maintaining the cuff pressure
(CP) during exercise and the rest interval also appears to
be an important variable in order to increase the metabolic demand in both type I and type II muscle fibers
[19]. As a result, the total number of repetitions performed in a training session can vary and is also determined by whether the first set of BFR exercise is to
volitional fatigue [18] or a predetermined number of
repetitions [20].
Overall, BFR exercise training studies have ranged
from 6 to 90 days in duration (Figure 1) and most show
dramatic muscular adaptations. For example, Fujita et al.
[21] reported 6.7% and 3% increases in KE strength and
size, respectively, after 6 days of twice-daily BFR knee
extension (KEx). Likewise, Yasuda et al. [22] demonstrated even larger improvements in 1RM SQT (14%)
and quadriceps muscle size (7.8%) from 2 weeks of
twice-daily BFR SQT exercise. Moreover, BFR SQT and
leg curl exercise performed 6 days per week for 2 weeks
resulted in approximately 17% and 22% increases in
SQT and leg curl 1RM, respectively, and an 8.5% increase in thigh cross-sectional area (CSA) [23]. Studies
implementing less frequent BFR resistance exercise sessions over longer training durations also show substantial muscular adaptations. Clark et al. (2011) observed
an 8% increase in KE strength after 4 weeks of BFR exercise (3 days per week), while Takarada et al. [24]
reported approximately 10% increases in KE strength

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45

KE CSA (% Change)

BFR Resistance Exercise

40

BFR Walking Exercise

35

BFR Cycling Exercise

30
25

20
15
22

10

23

KE Strength (% Change)

45
40
35
30
25
20
15
10
5
0

114

29
28

21

108
115
111

116
24
48 52
27
124
93

113
109

48

117
112

114
29
21

92

57

108

110

116
24
27

52
107

113

28

21

108

52

approximately 200 mmHg applied to the upper legs [2729]. Walk training studies showed that the metabolic
cost of walking is approximately 3% higher and that
heart rate (HR) is approximately 30 bpm higher during
walking with BFR compared to normal walking at the
same speed [29]. The training adaptations of 3-weeks of
twice-daily BFR walking training at 20% of VO2max
included an increase in leg press and leg curl 1RM of approximately 8% and an increase in upper leg CSA of approximately 6%. No changes in muscle size or strength
were observed in the control group that performed the
same walking protocol without BFR [28,29]. Similarly, 3
weeks of three times-per-week BFR cycling for 15 min at
40% VO2max resulted in increases in thigh CSA (3.4%),
KEx strength (7.7%), and VO2max (6.4%). The control
group cycled for 40 min at the same intensity and
showed no change in muscle strength or aerobic fitness
[27]. Traditionally, aerobic exercise is prescribed at approximately 75% of VO2max to elicit improvement in
aerobic fitness. BFR aerobic exercise not only improves
aerobic fitness at a low intensity, but also increases
muscle strength and size, which are not usually observed
following an aerobic training program.

20
40
60
80
100
BFR Exercise Training(d)

Figure 1 Relative change (%) KE muscle size and strength with

BFR exercise training. Numbers in the figure correspond to
reference citations [27,28,107-118].

and size over 8 weeks (2 days per week) of training.

When studies are statistically combined, mean effect
sizes ((post-mean pre-mean)/pre-standard deviation
and adjusted for sample size bias) [25] for muscle hypertrophy and strength for BFR resistance exercise are 0.39
and 0.58, respectively (compared to 0.01 and 0.000 for
low-load training without cuff inflation) [15]. An important difference between high-load and BFR training is
that increased muscle strength corresponds with muscle
hypertrophy within the first 4 weeks of BFR exercise
training, which is in contrast with the nervous system
adaptations that result in enhanced muscle strength over
the same duration of high-load resistance exercise training [26].
BFR aerobic training

Similar to BFR resistance training, the BFR aerobic exercise training studies couple low-intensity walking or cycling (approximately 20%40% of maximal oxygen
consumption, VO2max) with an external pressure cuff of

Mechanisms underlying BFR exercise training adaptations

Data from BFR exercise training studies demonstrate

that this novel exercise approach is gaining scientific
merit as a potential alternative to traditional resistance
exercise, and a growing body of literature is emerging to
suggest a potential to also improve aerobic fitness. There
was a recent surge in publications describing the underlying mechanisms associated with BFR resistance training adaptations; however, the physiological mechanisms
explaining the observed changes remain elusive.
Muscle metabolism, motor unit recruitment, and fiber
activation

Evidence suggests that type II muscle fibers are recruited

at a low load during BFR exercise [19]. A current hypothesis indicates that BFR resistance exercise causes
type I muscle fibers to fatigue quickly due to low oxygen
availability; hence, activation of type II muscle fibers and
a greater reliance on anaerobic metabolism are required
[14]. These events result in an accumulation of muscle
metabolites that stimulate the production of systemic or
local growth factors that initiate muscle protein transcription and translation [30-32]. A convincing evidence
for type II muscle fiber activation was demonstrated by
Krustrup et al. [19] who showed that phosphocreatine
concentrations in both slow and fast twitch fibers following BFR resistance exercise were reduced to an
equivalent concentration as compared to high-intensity
resistance exercise. However, fast twitch fiber recruitment evaluated by inorganic phosphate splitting

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occurred in only 31% of participants performing one set

of BFR resistance exercise compared to 70% of subjects
performing one set of high-load exercise [32]. When
multiple sets of BFR exercise were performed with continued BFR during the rest intervals, inorganic phosphate splitting was similar to multiple sets of high-load
resistance exercise [33]. Therefore, the overall effort and
threshold of fatigue reached during a session may facilitate the acute training response [34]. Further evidence
for insufficient oxygen availability and anaerobic type II
fiber activation exists in studies reporting enhanced
muscle biopsy lactate [35], blood lactate (La) [20], and
decreased pH [20] following BFR exercise compared to
exercise at the same load without external CP [30,31].
Systemic hormonal response

Anabolic and catabolic hormonal responses have been

frequently evaluated following acute and chronic BFR resistance exercise (Table 1). It is hypothesized that accumulation of metabolic by-products and/or the hypoxiainduced stimulation of afferent nerve fibers results in an
increase in secretion of the growth hormone (GH) and
GH-releasing hormone [36]. Takarada et al. [30] reported
that circulating GH concentrations following an acute bout
of BFR exercise were 290 times greater than the baseline;
however, Pierce et al. [37] showed a lower but still physiologically significant ninefold increase in GH concentration
using a similar protocol. A corresponding increase in the
circulating insulin-like growth factor-1 (IGF1) has been
observed during BFR KEx exercise (20% 1RM, four sets to
exhaustion, 160180 mmHg) and at 1030 min postexercise [36]. In contrast, the circulating IGF1 concentration was not increased up to 180 min following an acute

bout of BFR KEx exercise (20% 1RM, 200 mmHg, four sets,
75 total repetitions, 30-s rest periods) [20]. It is also argued
that the increase in IGF1 observed in some studies could be
related to a hemoconcentration as a result of plasma volume (PV) changes following BFR resistance exercise [13].
Following a training period, there was a report of a progressive increase in circulating IGF1 at rest following 2 weeks of
twice-daily BFR SQT and leg curl exercise (20% 1RM, three
sets, 15 repetitions/set, 30-s rest periods) [23]. Therefore,
the overall relationship between BFR resistance exercise
and the GH-IGF1 axis remains controversial.
The influence of acute and chronic BFR exercise on
other anabolic hormones such as testosterone (T) is also
unclear [38]. For example, neither Reeves et al. [39] nor
Fujita et al. [20] observed changes in total or free following arm or leg BFR resistance exercise, respectively. In
contrast, Madarame et al. [40] reported a post-exercise
elevation in total T following three sets of BFR KEx and
flexion. Chronic BFR walking [29] or resistance exercise
[41] has also failed to show resting changes in T. Worthy
of note, studies do show that circulating cortisol (Cort)
is elevated following BFR and high-load resistance exercise [20,40,42], which suggests a similar stress response.
However, circulating Cort concentration is primarily
associated with catabolism and muscle protein breakdown [43]. Recently, the overall association between the
acute systemic hormonal response to resistance exercise
and muscle hypertrophy has been questioned. West
et al. [44] reported no additional rise in muscle protein
synthesis or the phosphorylation of signaling proteins
following resistance exercise during elevated systemic
concentrations of T, GH, and IGF1 compared to low systemic concentrations of the same anabolic hormones.

Table 1 Systemic biomarkers and hormonal responses to an acute bout of BFR exercise
Reference
citation

Age (year)a

Exercise(s)

Intensity

Cuff width

CP (mmHg)

[39]

21

EF,PFx

30% 1RM

NR

20 SBP

[20]

32

KEx

20% 1RM

NR

200

Significant increase (p < 0.05)

No change (p > 0.05)

La, GH

T, Cort

La, GH, Cort

IGF1, T

[40]

26

EF,EE,KEx,KF

30% 1RM

30 450 mm

130200

[29]

21

Walking

50 m/min, 2 min

200 NR mm

200

GH

Cort

[30]

2022

KEx

20% 1RM

33 800 mm

214

La, NorEpi, GH, IL6

CK, LP

[119]

2540

EF

30%50% 1RM

90 700 mm

0100

[120]

2428

EF,EE,SQT,KF

20% 1RM

30 45 mm

190230

[121]

2022

KEx

30% 1RM

NR

200

La, NorEpi, GH

[37]

22

KEx

20% MVC

NR

280

GH

[21]

22

KEx

20% 1RM

NR

160220

[52]

21

EF,KEx,KF

30% 1RM

40 1,750 mm

>160

[42]

70

KEx

20% 1RM

NR

200

[36]

34

KEx

20% 1RM

33 880 mm

160180

La, Cort, NorEpi, GH, T

La
La, NorEpi, GH, Hemat

Na, K,

CK, Myo, IL6

GH, NorEpi

La, Cort, GH

Glu

La, NorEpi, GH, IGF1, VEGF

Ghrl

Age expressed as a mean, or if not available, as a range; CP cuff pressure, NR not reported, EF elbow flexion, PFx plantar flexion, KEx knee extension, EE elbow
extension, SQT squat, Myo myoglobin, La blood lactate, NorEpi norepinephrine, IL6 interleukin-6, LP lipid peroxidase, CK creatine kinase, pH blood pH, Cort cortisol,
IGF1 circulating insulin-like growth factor 1, T testosterone, Na sodium, K potassium, Myo myoglobin, Glu glucose, Ghrl ghrelin, VEGF vascular endothelial growth
factor.

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Hence, local factors may provide greater stimuli to induce BFR resistance exercise adaptations.
Gene expression and cell signaling

An acute bout of high-load resistance exercise elicits anabolic and catabolic responses that are altered in a complex
temporal manner to achieve muscle hypertrophy. Briefly,
muscle protein synthesis and myogenic gene transcripts
(e.g., myogenin) are upregulated within 2 h post-exercise
and peak approximately 8 h post-exercise, whereas proteolytic ligases (muscle-specific RING finger protein-1
(MuRF-1), Atrogin-1) are upregulated 14 h after exercise
and downregulated within 8 h of exercise termination
[45]. An approximate threefold increase in the phosphorylation of ribosomal protein S6 kinase beta-1 (S6K1), a
downstream component of the mammalian target of rapamycin (mTOR) signaling pathway and regulator of translation initiation and elongation, and a 46% increase in the
fractional synthesis rate (a measure of muscle protein synthesis) have been previously shown following BFR resistance exercise [20]. mRNA expression of genes that
regulate satellite cell activity (mechano-growth factor,
IGF1 receptor, myogenin, MyoD), cell size (myostatin),
and protein turnover (MuRF1, mTOR, S6K1) were not
different between BFR and low-load exercise up to 3 h
post-exercise [46]. At 8 h post-BFR or low-load exercise,
myogenic gene transcripts (IGF1, MyoD, and myogenin)
were not different from the baseline; however, proteolytic
transcripts (Atrogin-1, MuRF-1, and Forkhead box O3
(FOXO3A)) were downregulated twofold from baseline in
the BFR group only [47]. Following 8 weeks of BFR resistance training, myostatin gene expression was downregulated to a similar extent compared to high-load training
[48], with a trend (p = 0.06) toward decreased activin IIb
(myostatin receptor). There were also elevations in genes
associated with myostatin function (growth and differentiation factor-associated serum protein-1) and signaling
(SMAD family) [48]. Overall, the molecular pathways that
regulate BFR resistance exercise-induced muscle hypertrophy have not been extensively studied. Given that
muscle hypertrophy results from a positive net muscle
protein balance (synthesis > breakdown) across a training
period, greater examination of molecular events is needed
to better understand how BFR resistance exercise stimulates muscle growth.
The limitations and safety of BFR exercise
BFR exercise limitations

The application of BFR exercise appears to be limited to

peripheral muscle groups; thus, core, back, and neck
muscles cannot be specifically targeted using this methodology. Higher perceptual ratings of perceived exertion
and pain during the rest intervals of sets have also been
reported, which could limit the application of this

Page 5 of 13

training methodology [49]. The pressure applied to the

blood vessel during BFR exercise is likely the root cause
of discomfort and is associated with cuff width [17] and
the layer of soft tissue situated between the cuff and the
vessel [50]. The cuff sizes most frequently used in research studies are either narrow (approximately 5 cm) or
wide (approximately 13 cm). From the data, it appears
that lower cuff pressures (90120 mmHg) are required
to occlude venous blood flow when the wider cuffs are
used compared to the narrow cuffs (pressures, 160180
mmHg [51]. However, the narrow cuffs and associated
pressures have repeatedly been shown to cause improvements in muscle strength and size when combined with
low-load resistance exercise [52]. Exercise training adaptations have been observed with wider cuffs with the
same [53,54] or lower cuff pressures [55]; however, BFR
exercise performed at supra-systolic blood pressure
(SBP) with wider cuffs may restrict blood flow to a level
that reduces exercise volume and increases discomfort
compared to narrower cuffs [56]. Therefore, cuff width
is an important variable for determining BFR exercise
prescription and may be a limiting factor if not taken
into consideration with CP.
Hemostasis

The potential for blood coagulation and venous

thrombus following blood pooling is the most frequently
discussed (hypothesized) risk, and therefore, it has been
comprehensively evaluated in multiple acute studies
(Table 2). Most recently, Clark et al. [57] observed an increase in tissue plasminogen activator (tPA), a fibrinolytic
protein that catalyzes the conversion of plasminogen to
plasmin, immediately following a single bout of BFR exercise. This finding is consistent with those of Nakajima
et al. [58] who reported that an acute bout of BFR exercise
increased tPA antigen without altering plasminogen activator inhibitor-1 (PAI-1) or D-dimer (D-d). Together,
these results suggest that BFR exercise may acutely increase fibrinolytic activity, thus reducing the risk for blood
coagulation.
Acute cardiovascular stress

The acute cardiovascular responses to BFR exercise

training are important to consider because this type of
exercise could provide the greatest benefit for individuals
with a variety of health risks that preclude them from
performing traditional resistance exercise. Although
most BFR literature focus on muscular effects, it is important to note that resistance and aerobic BFR exercises
cause increases in HR and blood pressure that are
greater than those observed with exercise performed at a
similar intensity without BFR [29,59]. The increase in
HR is an important aspect of BFR exercise because it
allows cardiac output (CO) to be maintained, despite a

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Table 2 Hemostasis markers with acute BFR resistance exercise

Reference
citation

Exercise

Intensity

Sets (total repetitions)

CP (mmHg)

Cuff width (mm)

Significant increase
(p < 0.05)

No significant change
(p > 0.05)

[57]

KEx

30% 1RM

3 (2436)

1.3 *SBP

80 830

tPA

Fib, D-d, PTF

[20]

KEx

20% 1RM

4 (75)

200

NR

[42]

KEx

20% 1RM

4 (75)

200

NR

D-d

[122]

Leg press

30% 1RM

4 (75)

150160

65 650

PTF, TAT, D-d

[58]

Leg press

30% 1RM

4 (75)

172.5

NR

TAT, PTF 1,2, D-d

tPA

D-d, Fib, PAI-1

SBP systolic blood pressure, NR not reported, TAT thrombin-anithrombin complex, tPA tissue plasminogen activator, D-d D-dimer, Fib fibrinogen, PAI-1
plasminogen activator inhibitor-1, PTF prothrombin fragment 1,2.

decrease in venous return due to the CP [36]. Since

most BFR studies are conducted in healthy subjects, it is
important to evaluate the cardiovascular response to
BFR in individuals presenting with cardiovascular disease
risk factors in a controlled setting.
Muscle damage and reperfusion

Maintaining CP during the between-set rest interval is

one essential feature of the BFR exercise prescription. As
a result, higher levels of muscle soreness and perceived
exertion have been reported during and/or following
BFR-restricted exercise compared to the same lowintensity exercise performed without CP [60,61]. Delayed
onset muscle soreness is a common occurrence following eccentric muscle actions during high-load resistance
exercise [62]. In contrast, it appears that concentric
muscle actions compared to eccentric muscle actions result in greater muscle soreness following BFR resistance
exercise [60]. It is unclear why this is the case; however,
eccentric-induced muscle soreness is typically associated
with mechanical stress, which may be attenuated with
BFR exercise given the very low training loads. Systemic
physiological markers of BFR resistance exercise-induced
muscle damage are conflicting. Although neither creatine kinase nor myoglobin were elevated following two
BFR resistance exercise bouts [20,30], one case of
rhabdomyolysis has been reported in the literature [63].
In addition to the potential for muscle damage with
BFR training, there is a hypothetical risk for microvascular dysfunction as a consequence of the reperfusion that
occurs when blood flow is restored after a period of restriction or ischemia [64]. During reperfusion, there is an
acute release of inflammatory molecules, clotting factors,
and reactive oxidative species that impair microvascular
function [65]. Further, nitric oxide bioavailability (a mediator of vasodilation) decreases when blood flow is
restored, causing impaired arterial vasodilation and
increased sheer stress. Repeated reperfusion injury can
eventually cause a wound that influences endothelial
function. Renzi et al. [64] have shown a significant reduction in flow-mediated vasodilation 20 min after BFR
walking exercise, suggesting the potential for endothelial
dysfunction. Recent evidence also suggests increased

sarcolemma permeability (evidenced by staining of tetranectin) following BFR exercise, which may be caused by
cell damage from increased production of reactive oxygen species [66]. Furthermore, although not statistically
significant, Goldfarb et al. [67] showed that both protein
carbonyls and glutathione ratios (systemic indicators of
oxidative stress) were almost doubled following BFR resistance exercise in seven male subjects. Given that the
time course of reactive oxygen species generation was
limited to 15 min post-exercise, it is essential that future
acute studies have a sufficiently high number of subjects
and extended time courses.
Overall, BFR exercise training encompasses a variety of
new variables (cuff width, CP, cuff inflation duration) for
exercise prescription, and understanding these interactions in terms of safety is complex [68]. To date, the most
comprehensive data set on side effects from BFR exercise
training was established using survey methodology. The
most reported incidents from approximately 13,000
people participating in KAATSU training were as follows:
bruising (13.1%), numbness (1.3%), cerebral anemia
(0.3%), cold feeling (0.1%), pulmonary embolism (0.01%),
rhabdomyolysis (0.01%), deterioration of ischemic heart
disease (0.02%), and venous thrombus (0.06%) [69].
BFR exercise in spacepotential applications

Crewmembers commonly experience losses in aerobic

capacity and muscular strength following long-duration
spaceflight. Crewmembers that perform daily moderateto high-intensity exercise throughout the mission duration generally return in considerably better condition
than their counterparts that engage in little or lowintensity activity. Exercise with BFR may provide a
means to perform resistance exercise with a low load or
perform aerobic exercise at a slower walking speed or
lower pedaling resistance in the event of ISS exercise
hardware failure or in future exploration missions with
less robust exercise hardware.
Muscle size, strength, and endurance

Cook et al. [70] recently showed that KE CSA was maintained (1%) in a group that performed BFR resistance
exercise over a 30-day period of lower-limb unloading

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compared to a non-exercise control group (7.5%). Similarly, maximal voluntary contraction (MVC) was also
preserved in the BFR resistance exercise group (2%),
while the control group exhibited a 15.6% decline. Surprisingly, the BFR group also had a 28% increase in submaximal (approximately 40% MVC) muscular endurance
compared to a 24% decline in controls. These results
suggest that BFR resistance exercise may be an effective
exercise countermeasure to prevent losses in KE size
and strength while simultaneously improving muscular
endurance [70].
The plantar flexors are another major muscle group
susceptible to atrophy during unloading with the greatest plasticity evident in the soleus. For example, following 6 months on the ISS, soleus muscle size declined by
18% [71-73] and was accompanied by a decrement in PF
peak torque of 20%29% across the velocity spectrum
[73]. Even more concerning is that these results were
evident despite the performance of resistance and aerobic exercise countermeasures [73]. It is hypothesized
that the improved loading capability (273 kg) of ARED
onboard the ISS will mitigate future changes in soleus
muscle size and attenuate atrophy of other muscle
groups. However, the soleus muscle is best isolated when
the knees are flexed, which reduces the contribution of
the gastrocnemius to the muscle action [74]. Currently,
this motion is difficult to reproduce using ARED because movements are primarily performed in the standing position. Another problematic aspect of targeting the
soleus is a limited range of motion. As loads are
increased during plantar flexion exercise, the range of
motion can decrease substantially. Thus, because BFR
resistance exercise is performed using low training loads,
it may be possible to exercise throughout a crewmembers' full anatomic range of motion to more effectively
target the soleus. Although BFR resistance exercise has
not yet been performed in an unloading analog, a recent
ground-based study showed a 30% increase in PF MVC
following 4 weeks of training; these findings help to substantiate its potential application as a countermeasure to
unloading [55].
Orthostatic challenge

BFR exercise is also a potential countermeasure to orthostatic intolerance [75-77], a condition reported to occur in
up to 30% of astronauts returning from brief space shuttle
flights of 410 days [78] and in 80% of astronauts following long-duration missions [79]. During exposure to
microgravity, blood volume (BV) shifts from the capacitance vessels of the lower body to those in the face and
head. Upon return to 1-G, there is excessive pooling in
the lower limbs, resulting in orthostatic hypotension and
syncope [80]. Research has shown that elastic cuffs worn
on the upper thighs during flight help to maintain central

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and peripheral hemodynamics and mitigate post-flight

orthostatic intolerance [81]. However, the ability of these
cuffs to completely mitigate cardiovascular deconditioning
during spaceflight has not been definitively determined
[82]. It is hypothesized that the most effective in-flight
countermeasure would be a gravity-like stimulus, such as
lower body negative pressure (LBNP). Exercise with LBNP
of 1.0 to 1.2 times body weight during 6 head-down-tilt
(6HDT) bed rest has been shown to maintain upright exercise capacity [83].
BFR exercise elicits several features that are similar to
LBNP including lower extremity blood pooling, decreased
venous return, and increased autonomic activation [75].
Nakajima et al. [75] showed that restriction of blood flow
reproduces the effects of standing on HR, stroke volume
(SV), and norepinephrine release, thus simulating a
gravity-like stress during short-duration 6HDT bed rest.
Furthermore, Kubota et al. [76] demonstrated that BFR resistance exercise during short-duration 6HDT bed rest
elicits hemodynamic and neurohumoral responses that
approximate a gravity-specific stress on the cardiovascular
system. In the before-mentioned study, subjects participated in 24 h of 6HDT bed rest resulting in 4.4% and
7.8% losses of BV and PV, respectively. Subjects performed
BFR leg press resistance exercise (30% 1RM, four sets, 30/
15/15/15 repetitions, 1-min rest intervals, 65 650-mm
cuff width, 150160 mmHg CP), while remaining at
6HDT. SV was significantly reduced during BFR resistance exercise and was similar to the measurement
obtained when standing. These results suggest that frequent applications of BFR exercise during microgravity
may provide a stimulus to the cardiovascular system that
simulates 1-G, which may reduce post-flight orthostatic
intolerance. Future investigations should examine the impact of BFR exercise during long-duration bed rest on the
physiological responses to orthostatic stress.
BFR exercise in spaceunanswered questions

To date, the majority of evidence for the application of

BFR in space stems from research exploring skeletal
muscle physiology during acute or chronic exercise studies. Few BFR studies have focused on the acute effects or
training adaptations on cardiovascular or skeletal health.
Since exposure to microgravity compromises human
physiology in a variety of ways, there is a clear need to
expand the scope of BFR research to include other
physiological systems.
Cardiovascular health

Cardiac mass decreases to levels that are well below normal in conditions of weightlessness and simulated
weightlessness. Perhonen et al. [84] demonstrated that
left ventricular mass (measured by magnetic resonance
imaging) decreased by 15% during prolonged supine bed

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rest and by 12% after short-duration spaceflight. It

appears as though disuse-induced cardiac atrophy does
not influence systolic function [84]; however, one of the
most important clinical consequences of cardiac atrophy
may be its influence on diastolic function. Invasive studies of cardiac performance before and after 2 weeks of
6HDT bed rest have shown that there is a leftward shift
in the diastolic pressure-volume curve after bed rest,
resulting in a smaller left ventricular end-diastolic volume for a given filling pressure [85]. Because the effects
of BFR on cardiac morphology and function have not yet
been investigated, it is unclear if this form of exercise
could provide the stimulus required to completely prevent cardiac deconditioning. The novelty of BFR appears
to be the unique combination of venous BV pooling and
restricted arterial blood inflow, resulting in a decreased
SV and increased HR, while maintaining CO [36]. Consequently, in contrast to traditional aerobic exercise [86],
eccentric loading of the heart and prevention of cardiac
atrophy may not occur during BFR exercise.
Previous studies have established that deconditioning
leads to detrimental vascular changes such as endothelial
dysfunction, decreased arterial compliance, and atherosclerosis [87,88]. Hesse et al. [89] found that 13 days of
bed rest impaired endothelium-dependent arterial relaxation in healthy men, while Tuday and colleagues [88]
reported that spaceflight significantly reduced vessel
compliance [88]. Alternatively, cross-sectional studies
using middle-aged and older adults have found that
regular aerobic exercise improves arterial compliance
[90,91]. As previously mentioned, although BFR exercise
appears to acutely decrease endothelial function [64],
the chronic effects of BFR exercise remain equivocal.
Kim et al. [92] found that arterial compliance of the
large and small arteries was not affected by 4 weeks of
BFR resistance training. Conversely, Ozaki et al. [93]
reported that carotid arterial compliance was improved
by 10 weeks of BFR walk training in elderly subjects.
Given that reduced endothelial function and arterial
compliance are early markers of atherosclerosis [94],
surrogate markers of cardiovascular function [95], and
predictors of future cardiovascular complications
[96,97], further examination of both the acute and
chronic effects of BFR exercise on vascular health is
needed.
Skeletal health

In addition to the cardiovascular consequences associated

with prolonged spaceflight, bone health is a primary concern. Bone demineralization occurs predominately in the
long bones of the lower limbs, with maximal bone loss occurring in the calcaneus and the hip [98]. Skeletal unloading in astronauts can result in losses of 1%2% per month
in bone mineral density [99,100]. On the Mir year-long

Page 8 of 13

mission, bone measurements of astronauts showed a 10%

reduction of the lumbar vertebrae [101]. Despite having a
lower mechanical load during training, there is some evidence in ambulatory subjects that BFR resistance training
may be beneficial to bone. For instance, after an acute
bout of BFR resistance exercise in young men, there was a
significant reduction in bone resorption as evidenced by
serum N-terminal cross-linking telopeptide of type I collagen [102]. Six weeks of BFR resistance exercise training in
older men also showed a 21% increase in serum bonespecific alkaline phosphatase, a marker of bone formation
[102]. Although the mechanism for how low-load BFR resistance exercise improves bone parameters has not been
clearly established, Loenneke et al. (2012) indicate that
BFR exercise may induce physiological responses as a result of interstitial fluid flow-induced sheer stress within
the osteocyte membrane [103] and/or the activation of
vascular endothelial growth factor via the hypoxia inducible transcription factor pathway [104]. Further work is
needed to determine how BFR training could protect bone
health during prolonged unloading.
Perspectives

A BFR exercise training device and Russian Braslet cuffs

are currently onboard the ISS. To our knowledge, these
devices have not been used with exercise by ISS crewmembers. However, BFR exercise may have already been
inadvertently performed by US astronauts on Skylab. In
a recent historical account, it was noted that during the
first few days of the mission, astronauts had significant
problems adhering to the exercise workloads prescribed
on the cycle ergometer [105]. At low intensities, no
issues were observed; however, at high intensities, workloads could not be reached and the astronauts described
significant leg fatigue and discomfort [105]. The root
cause was the combination of a padded waist belt and
shoulder harness that restricted circulation to the legs as
training loads increased. A solution to the problem was
eventually implemented, but it is plausible that the
restricted circulation these crewmembers experienced
was similar to the BFR cycling methods that have been
recently evaluated by researchers [27].
Overall, it is unlikely that BFR exercise will be used as
a standalone exercise countermeasure onboard the ISS
given the significant presence of ARED among other
more traditional exercise devices. However, in future
space exploration missions beyond the ISS, both aerobic
and resistance BFR exercise trainings may be given some
consideration depending on the vehicle capacity and the
capability of onboard exercise devices. Combining lowload BFR resistance exercise with the current moderateto high-load could help attenuate skeletal muscle atrophy without excessive loading of the shoulders, lower
back, and/or joints. Specifically targeting the plantar

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Page 9 of 13

flexors with BFR resistance exercise training may be an

alternative method to prevent soleus atrophy and dysfunction. Research also suggests that BFR exercise may
simulate the cardiovascular response to standing in 1-G,
which could potentially reduce orthostatic intolerance
upon return to earth. However, few studies have evaluated BFR exercise using a chronic ground-based unloading analog (Table 3), and only two acute studies have
used 6HDT bed rest, which is the analog that reflects
the fluid shift observed during spaceflight.
Future work should evaluate the safety of exercise prescription and determine the influence of new programming variables (e.g., leg CIRC, adipose tissue thickness,
CP, and cuff width) on human physiology. Once acute
exercise prescription is understood, BFR exercise should
be evaluated across multiple physiological systems using
long duration 6HDT bed rest. Measuring cardiovascular and skeletal outcomes in addition to skeletal muscle
parameters during prolonged unloading is essential to
enhance our understanding of the effects of this novel

method of exercise. Furthermore, because BFR exercise

training has implications for sarcopenia and other
muscle wasting conditions, a mechanistic understanding
of the cellular pathways resulting in muscle growth
would be beneficial [106].

Conclusion
Researchers should be commended for their pioneering
efforts in understanding the mechanistic and adaptive
responses to BFR exercise. Both BFR resistance and aerobic exercise prescription appear to be in early stages of
development relative to traditional resistance and aerobic training. Currently, low-load BFR resistance exercise increases muscle size and strength in ambulatory
participants and attenuates muscle atrophy and strength
loss during periods of unloading. Low-intensity BFR aerobic exercise while ambulatory enhances muscle size
and strength and simultaneously increases aerobic fitness. As the science behind BFR exercise training
matures in the future, it is evident that this type of

Table 3 Restriction of blood flow and BFR exercise while supine or using musculoskeletal unloading models
Reference
citations

Method(s)

Highlighted outcome(s)

Limitation(s)

[75]

KAATSU (65 650-mm cuff, 50100 mmHg, 24 h of 6HDT bed rest resulted in body
no muscle contractions, 10 min) following mass,BV, PV, and IVCd; 10 min of
24-h 6HDT bed rest
50 mmHg, KAATSU: HR, SV, CO, IVCd,
Hct, Hb, BV, and PV. Authors
suggest that KAATSU reproduces the effect
of a gravity-like stress during simulated
weightlessness

[76]

KAATSU (65 650-mm cuff, 150160

mmHg) with 6HDT leg press resistance
exercise (30% 1RM, four sets, repetitons:
30/15/15/15, 1-min rest between sets)
following 24-h 6HDT bed rest

24 h of 6DHT bed rest: body mass, BV,

PV, and Hct. KAATSU + 6DHT leg press
resistance exercise:HR, BP, SV, and CO.
Authors suggest that KAATSU with leg press
exercise mimics the exercise hemodynamic
response to exercise in 1-G

Potential conflict of interest between the

KAATSU device and the journal publishing
the research study

[77]

Supine with KAATSU (60 605 mm,

200 mmHg, no muscle contractions vs.
standing)

Supine with KAATSU: SV, HR, TPR, and

CO. Authors suggest that KAATSU induced
hemodynamics similar to standing

Case study: potential conflict of interest

between the KAATSU device and the
journal publishing the research study. Fluid
shift stimuli are not introduced

[123]

Supine with KAATSU (60 605 mm,

50250 mmHg, no muscle contractions vs.
standing)

Supine with KAATSU: FVd, FBf, IVCd,

Fluid shift stimuli are not introduced
LVDd, CO, HR, and TPR. Authors suggest
that KAATSU induced hemodynamics similar
to standing

[70]

BFR (60 830 mm, 150 mmHg) KEx

resistance exercise (20% MVC, three sets,
repetitons to fatigue 1.5-min rest between
sets) during 30 days of unloading via ULLS

Following 30 days of ULLS: KE CSA, KE

endurance, PF CSA, PF MVC, IGF1, and
IGFBP3. Authors suggest that BFR exercise
is effective in maintaining muscle size and
strength and improving muscular endurance
during unloading

Fluid shift stimuli are not introduced. ULLS

model may not be appropriate for systemic
blood markers

[124]

Restriction of blood flow (77 770 mm,

200 mmHg, five sets, 5-min bouts,
3-min rest between sets during 14 days of
cast immobilization

Restriction of blood flow: KE MVC, PF

CON60,leg/thigh CIRC, and GH. Authors
suggest that restriction of blood flow to the
lower extremity prevents disuse muscular
weakness

Fluid shift stimuli are not introduced. Cast

immobilization model differs from
spaceflight musculoskeletal unloading due
to joint mobility

One subject developed neurocirculatory

presyncope 5 min after 100 mmHg
KAATSU. There were no symptoms in the
remaining seven subjects

BFR blood flow-restricted, BV blood volume, PV plasma volume, IVCd inferior vena cava diameter, HR heart rate, SV stroke volume, CO cardiac output, Hct
hematocrit, Hb hemoglobin, TPR total peripheral resistance, FVd femoral vein diameter, FBf femoral arterial blood flow, LVDd left ventricle end-diastolic dimension,
KE knee extensor, CSA cross-sectional area, CIRC circumference, PF plantar flexor, CON60 concentric 60 sec1, MVC maximal voluntary contraction, IGF1 circulating
insulin-like growth factor, IGFBP3 circulating insulin-like growth factor binding protein-3, GH growth hormone, 1RM one repetition maximum, 6HDT 6 headdown-tilt bed rest, ULLS unilateral lower limb suspension, decreased, increased, no change.

Hackney et al. Extreme Physiology & Medicine 2012, 1:12

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training could be applicable as an adjunct countermeasure to combat musculoskeletal and cardiovascular dysfunctions during missions beyond low-earth orbit.
Abbreviations
1RM: One repetition maximum; 6HDT: 6 head-down-tilt; ARED: Advanced
resistive exercise device; BFR: Blood flow restricted; BV: Blood volume;
CIRC: Circumference; CK: Creatine kinase; CO: Cardiac output;
CON60: Concentric 60 sec1; Cort: Cortisol; CP: Cuff pressure; CSA: Crosssectional area; D-d: D-dimer; EE: Elbow extension; EF: Elbow flexion;
FBf: Femoral arterial blood flow; Fib: Fibrinogen; FOXO3A: Forkhead box O3;
FVd: Femoral vein diameter; Ghrl: Ghrelin; Glu: Glucose; GH: Growth
hormone; Hb: Hemoglobin; Hct: Hematocrit; HR: Heart rate; IGF1: Insulin-like
growth factor-1; IGFBP3: Circulating insulin-like growth factor binding
protein-3; IL6: Interleukin-6; ISS: International Space Station; IVCd: Inferior
vena cava diameter; K: Potassium; KE: Knee extensor; KEx: Knee extension;
La: Blood lactate; LBNP: Lower body negative pressure; LP: Lipid peroxidase;
LVDd: Left ventricle end-diastolic dimension; mTOR: Mammalian target of
rapamycin; MuRF-1: Muscle-specific RING finger protein-1; MVC: Maximal
voluntary contraction; Myo: Myoglobin; Na: Sodium; NorEpi: Norepinephrine;
NR: Not reported; PAI-1: Plasminogen activator inhibitor-1; PF: Plantar flexor;
PFx: Plantar flexion; pH: Blood pH; PTF: Prothrombin fragment 1,2; PV: Plasma
volume; S6K1: Ribosomal protein S6 kinase beta-1; SBP: Systolic blood
pressure; SQT: Squat; SV: Stroke volume; T: Testosterone; TAT: Thrombinanithrombin complex; tPA: Tissue plasminogen activator; TPR: Total
peripheral resistance; ULLS: Unilateral lower limb suspension; VEGF: Vascular
endothelial growth factor.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
KH outlined a draft of the proposal and synthesized contributions from all
authors. KH, ME, JS, and LPS wrote, revised, and edited the manuscript. All
authors read, edited, and approved the final version of the manuscript.

Page 10 of 13

10.

11.

12.
13.

14.

15.

16.
17.

18.

19.

20.

21.
Acknowledgments
We would like to thank all members of the NASA Exercise Physiology &
Countermeasures Project, Lyndon B. Johnson Space Center, Houston, Texas
for their support of this work.
Author details
Wyle Science, Technology and Engineering Group, Houston, TX 77002, USA.
2
University of Houston, Houston, TX 77002, USA. 3Universities Space Research
Association, Houston, TX 77002, USA.

22.

23.

Received: 20 April 2012 Accepted: 5 September 2012

Published: 1 December 2012
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doi:10.1186/2046-7648-1-12
Cite this article as: Hackney et al.: Blood flow-restricted exercise in
space. Extreme Physiology & Medicine 2012 1:12.

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