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Blood Flow - Restricted Exercise in Space 2012
Blood Flow - Restricted Exercise in Space 2012
REVIEW
Open Access
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
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
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.
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45
KE CSA (% Change)
40
35
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)
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
Page 4 of 13
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
La, GH
T, 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
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
La, NorEpi, GH, Hemat
Na, K,
La, Cort, GH
Glu
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.
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
Page 5 of 13
Page 6 of 13
Exercise
Intensity
CP (mmHg)
Significant increase
(p < 0.05)
No significant change
(p > 0.05)
[57]
KEx
30% 1RM
3 (2436)
1.3 *SBP
80 830
tPA
[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
[58]
Leg press
30% 1RM
4 (75)
172.5
NR
tPA
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.
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
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
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
Page 7 of 13
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
Page 8 of 13
Page 9 of 13
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]
[77]
[123]
[70]
[124]
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.
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.
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