Effect of Blood Flow Restriction on Cross-Education of Muscle Strength and Volume: A Systematic Review and Meta-Analysis

Key Points

• Blood flow restriction training stimulated cross-education of muscle strength, but its effect on muscle volume has not been confirmed.

• Reduced exercise intensity during blood flow restriction training may enhance neural activation.

• Rehabilitation that combines neural mechanism–based and cross-education training for patients with neurological disorders should be studied.

Blood flow restriction training (BFR), also known as Kaatsu, was developed by Dr Yoshiaki Sato in Japan as a novel method to enhance muscle strength and exercise performance.¹ It involves partially restricting arterial blood flow and fully restricting venous return from the muscles to the heart during exercise without completely obstructing blood circulation.^2,3 Using pressure cuffs on the limbs, clinicians can integrate BFR with diverse exercises, yielding substantial benefits in rehabilitation, muscle strengthening, and hypertrophy. Blood flow restriction training is applied across a spectrum of individuals, including athletes, the generally healthy, and the middle-aged to older population.⁴ In controlled settings, BFR is considered a safe practice for the overall healthy population. However, individuals with cardiovascular conditions, such as heart disease and hypertension, should seek the guidance of their health care professional, who can carefully assess whether they can engage in BFR training and help formulate a training regimen.^4–6 Researchers have combined BFR with resistance exercise, aerobic exercise, or a blend of both; innovatively merged electromyographic with neuromuscular stimulation; and incorporated whole-body vibration.² Compared with isolated low-intensity load training, the integration of BFR has been shown to enhance muscle strength and hypertrophy more effectively.⁵

Cross-education (CE) is characterized by a marked enhancement in strength and adaptability of the contralateral, untrained limb after unilateral limb training.⁷ The underlying mechanism of CE remains a focal point of research, with competing hypotheses including neural and myogenic mechanisms, but a consensus has not been reached. Although initial theories posited myogenic mechanisms as the cause of CE,⁸ subsequent research has indicated an absence of substantial size changes in contralateral homologous muscles, suggesting a neurogenic mechanism.^9,10 Bilateral access and cross-activation represent 2 theoretical models explaining the neural mechanisms, wherein both the brain and spinal cord are implicated.¹¹ The bilateral-access model posits that the movement patterns in unilateral activities are mirrored by attempting to perform identical tasks on the opposite side of the body.¹² The cross-activation model demonstrates that adaptations from unilateral movements can transfer to the contralateral side of the body.¹³ Although consensus regarding the mechanism of CE is lacking, the characteristics and potential applications of CE have been extensively investigated. Cross-education can manifest in various muscle groups, including those of the upper limb, such as the rotator cuff, select elbow flexors, and wrist flexors,^14–16 and the lower limb, such as certain ankle dorsiflexors and knee extensors.¹⁷ Several techniques effectively facilitate CE, such as neuromuscular electrical stimulation,¹⁸ targeted electroacupuncture,¹⁹ and independent muscle-contraction exercises.²⁰ The prevalent approach involves using conventional resistance training as a catalyst by modulating load intensities, training volumes, and contraction techniques.^21,22 Nonetheless, investigations of BFR techniques for induction remain comparatively limited.^23–28 In recent years, the application of CE in clinical settings has expanded, particularly in the early rehabilitation of unilateral neurological conditions such as stroke. Cross-education not only aids in preventing complications but also enhances muscle strength and function in the affected limb. Initiating contralateral training early after anterior cruciate ligament reconstruction may enhance the recuperation of quadriceps-muscle strength after the procedure.¹⁷ The clinical application of CE is progressively broadening, encompassing both neurological and orthopaedic conditions.

Although uncertainties about the mechanisms of CE effects exist, the indispensable role of CE in certain clinical rehabilitation populations is evident. Blood flow restriction training is simpler and more patient friendly than traditional methods used to induce CE effects. The nervous system serves as the conduit for CE effects, with substantial evidence pointing to the untrained hemisphere as the primary mediator, despite incomplete knowledge of the specific cortical and neurophysiological adaptations.²⁹ However, these cortical adaptations ultimately occur at the motor-unit level.³⁰ In general, the initial increase in muscle strength is greatly influenced by the activation patterns of motor units, whereas later stages are associated more with maximal muscle strength.^31–33 Blood flow restriction can notably improve neuromuscular adaptability.^34–39 However, experimental studies are lacking on whether this enhanced adaptation can be transferred to the untrained side and the extent to which it can be preserved. Considering the test population, individuals without previous training experience, who have greater potential for neuromuscular improvement, may benefit more from BFR in enhancing motor-unit recruitment than from traditional resistance training. However, for elite professional athletes, the marginal gains offered by this method may appear insignificant. From a neural mechanism standpoint, the general population aligns well with the training principles of BFR and CE, presenting ample opportunity for enhancement. Injured athletes may find this training more suitable for preserving their skill level and decelerating the decline in muscle strength.

Cross-education effects are typically more pronounced after high-load exercise, with evidence indicating that high-load exercise at 70% of 1-repetition maximum (1RM) yields greater benefits than low-load exercise at 30% of 1RM.^21,40,41 However, for certain populations, such as patients undergoing clinical rehabilitation or middle-aged and older patients, high-load lifting may be impractical. Therefore, identifying effective strategies to enhance the efficacy of low-load exercises is crucial for these individuals. Integrating BFR with low-load exercise could amplify CE benefits to match those achieved with high-load exercise.^42,43 Blood flow restriction has demonstrated a more substantial increase in muscle size and strength compared with conventional equal-load exercise.⁴⁴ In conclusion, CE could potentially yield superior outcomes when coupled with BFR.

Investigation into whether BFR can augment CE benefits is still nascent. Current research on this topic typically involves small sample sizes, with approximately 10 participants per group, and lacks a systematic analysis.^42,43 Therefore, the purpose of our study was to use a meta-analytic approach to systematically assess whether low-load BFR can facilitate CE of muscle strength and volume, offering empirical support for clinicians and rehabilitation specialists.

METHODS

RESULTS

Study Selection

A total of 1729 articles were retrieved, and 519 duplicate records were excluded. After reading the titles and abstracts of 1210 studies, we excluded 1202 studies and downloaded the full text of 8 articles. Six articles were included in the meta-analysis.^{42,43,48–51} The literature screening process is shown in Figure 1.

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Study Characteristics

Study characteristics are provided in the Table. The sample size of 306 individuals comprised 154 men and 152 women. Three studies exclusively involved men,^42,48,51 1 focused solely on women,⁴³ and 2 encompassed both sexes.^49,50 The average age of participants ranged from 21.5 to 24.8 years. All studies quantified variable resistance, with the BFR group consistently using a low load between 20% and 50% 1RM. In 2 studies, the control group used loads varying from low (75% of 1RM) to high (100% of MVC).^49,50 Three studies^42,43,49 included a blank control group, 3 studies^48,50,51 included a non-BFR unilateral training control, and 3 studies^42,43,49 implemented both control types concurrently. Intervention duration ranged from 4 to 10 weeks, with sessions held 2 to 5 times weekly postintervention. Muscle strength and volume were assessed in all studies.

Table.Study Characteristics

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Study Quality and Reporting

Using the Cochrane risk-of-bias assessment tool, we rated all 6 articles as having a high risk of bias. Figure 2 illustrates the results of the evaluation.

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Meta-Analysis

We included 3 intervention studies in the meta-analysis of CE benefits of BFR versus a blank control group on contralateral muscle strength.^42,43,49 All studies tested muscle strength at different times, with a total of 3 comparisons. The meta-analysis results showed no heterogeneity (I² = 0%, P = .73), with a combined effect size of SMD = 0.59 (95% CI = 0.24, 0.94), indicating a difference (P = .001; Figure 3).

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In the meta-analysis of CE benefits of BFR versus unilateral resistance training on contralateral muscle strength, 5 intervention studies were included and tested muscle strength at different times, with a total of 8 comparisons.^42,48–51 The meta-analysis results showed no heterogeneity (I² = 36%, P = .14), with a combined effect size of SMD = 0.29 (95% CI = 0.06, 0.52), indicating a difference (P = .01; Figure 4).

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We included 3 intervention studies in the meta-analysis of CE benefits of BFR versus a blank control group on contralateral muscle volume.^42,43,49 All studies tested muscle strength at different times, with a total of 3 comparisons. The meta-analysis results showed no heterogeneity (I² = 0%, P = .98), with a combined effect size of MD = −0.01 (95% CI = −0.06, 0.04), which was not different (P = .60; Figure 5).

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In the meta-analysis of CE benefits of BFR versus unilateral resistance training on contralateral muscle volume, 5 intervention studies were included and tested muscle volume at different times, with a total of 5 comparisons.^42,48–51 The meta-analysis results showed no heterogeneity (I² = 0%, P = .93), with a combined effect size of MD = 0.01 (95% CI = −0.04, 0.06), indicating no difference (P = .64; Figure 6).

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DISCUSSION

Few researchers have comprehensively evaluated the effects of BFR on CE of muscle strength and volume using quantitative analysis. We analyzed the effects of BFR by comparing a BFR training group with a blank control group and a unilateral resistance training group, focusing on changes in muscle strength and cross-sectional area. The aim was to optimize clinical rehabilitation prescriptions and enhance muscle function in patients undergoing rehabilitation and middle-aged or older individuals.

After comparing the growth of contralateral muscle strength between the BFR group and the blank control group in 3 studies, we concluded that BFR induced CE of muscle strength.^42,43,49 Therefore, we need to explore whether BFR has an advantage over unilateral resistance training in increasing contralateral muscle strength and is worth choosing over conventional unilateral resistance training despite certain risks.

Of the 5 studies included in the meta-analysis comparing the BFR group with the unilateral resistance training group, 3 studies^42,48,49 indicated a notably greater CE of muscle strength with BFR, and 2 other studies^50,51 yielded contrasting findings. Previous systematic reviews demonstrated that high-load exercises induce greater CE effects compared with low-load-intensity exercises.^52,53 In our study, only Mendonca et al used high-intensity resistance training in the control group.⁵⁰ This could explain why they reported contrary findings; they compared the growth of contralateral muscle strength between low-intensity BFR (20% of 1RM) and high-intensity unilateral resistance training (75% of 1RM). Their findings indicated that although low-load unilateral training may exhibit greater CE compared with low-load unilateral training, it may not be as effective as high-intensity unilateral training. In their 2017 meta-analysis, Hughes et al reported that BFR led to improvements in muscle strength, muscle cross-sectional area, and physical function in older adults compared with a blank control group, with average strength gains ranging from 2.9% to 35.6%, increases in muscle cross-sectional area ranging from 3.1% to 8.0%, and improvements in functional testing ranging from 12% to 28%.⁵ However, they also indicated that, although BFR effectively enhances strength in older adults as demonstrated by Cook et al, this increase is not as great as that achieved through high-intensity unilateral resistance training.⁵⁴ This conclusion does not necessarily affect the use of unilateral BFR in clinical rehabilitation. Blood flow restriction training can effectively enhance muscle strength in individuals who cannot tolerate high-load training or for whom it is contraindicated; relieve pain; and prevent muscle atrophy and strength decline in patients who are bedridden and older adults.

Madarame et al randomly selected the dominant or nondominant side for intervention training in the experimental group, whereas other researchers focused solely on the dominant hand.⁵¹ However, the hemisphere function of the brain is asymmetrical, with researchers noting higher corticospinal excitability⁵⁵ and shorter transcallosal conduction delay in the dominant hemisphere.⁵⁶ During unilateral movement, the inhibitory effect of the dominant hemisphere on the nondominant hemisphere outweighs the reverse.^56–58 The dominant hemisphere exhibits greater involvement in nondominant movement and tends to interfere with mirror movements generated by the excitatory output of the nondominant hemisphere.^56–58 Therefore, although both limbs bear equal loads during unilateral training, the dominant limb is disproportionately stimulated, leading to increased limb asymmetry, particularly evident during complex multijoint exercises. This discrepancy may account for the lack of difference in CE observed between the BFR group and the unilateral resistance training group.

Based on the above content, we conservatively conclude that in clinical settings, BFR can be prioritized to induce contralateral muscle strength. For individuals who cannot undergo high-intensity unilateral resistance training to promote contralateral muscle-strength recovery, BFR is a more suitable and effective choice.

In practical applications, the magnitude of CE is correlated with the muscle-strength increment on the trained limb, with the strength increase on the opposite side being approximately 60% of that on the same side.^59–61 Therefore, in assessing the CE phenomenon, one can gauge enhancement in muscle strength on the contralateral side by monitoring the strength increase on the ipsilateral limb, facilitating a prompt and convenient evaluation of the therapeutic effect. Furthermore, this evaluation allows for a scientific determination of training volume for the advantaged limb, enhancing the overall efficacy of the rehabilitation plan, thereby increasing the strength of the contralateral muscle and achieving the desired rehabilitative outcome.

Regarding muscle volume, the results of the meta-analysis indicated no difference between experimental and control groups. Of the 3 studies^42,43,49 including a blank control group for comparison, 2 studies^42,43 showed an increase in or maintenance of contralateral muscle volume (Figure 5). Four of 5 studies including a unilateral resistance training group for comparison reached the same conclusion (Figure 6).^42,49–51

Hortobágyi et al indicated that the maintenance of muscle volume relies on a delicate balance between muscle protein synthesis and degradation.⁶² Muscle atrophy occurs when protein degradation surpasses synthesis, and CE has been proven effective in reducing muscle atrophy.⁶² Researchers have suggested that the protective effect of CE on skeletal muscle mass depends on synergistically activating protein synthesis pathways, inhibiting protein degradation pathways, or both.¹¹ Another hypothesis is that training the contralateral limb inhibits protein degradation pathways instead of activating protein synthesis pathways. This effect may not be detected under stable conditions of basic protein degradation but can be substantial in severe muscle atrophy, thus preventing disuse-induced muscle atrophy. The mechanism underlying increased strength and muscle hypertrophy during BFR remains unclear. Evidence in multiple studies has suggested that it could be due to indirect effects, including the response of muscle cells to swelling and the accumulation of metabolites, possibly triggered by the biochemical stress response and metabolite buildup during exercise.^63–65 These effects may lead to the recruitment of more type 2 muscle fibers, enhancing muscle activation through fatigue and improving training efficiency. Concurrent metabolic stress response and tissue hypoxia also promote the expression of hypoxia inducible factor-1α and vascular endothelial growth factor.^35,38 Furthermore, muscle-fiber swelling facilitates cell protein synthesis via mechanistic target of rapamycin/ribosomal protein S6 kinase 1–mediated mammalian targeting pathways and satellite cell migration to muscle fibers.^36,37 The augmentation of these responses ultimately leads to muscle hypertrophy and increased skeletal muscle capillaries.^34,39 Therefore, based on previous evidence regarding the effects of CE or BFR on muscle volume, a BFR-induced CE phenomenon could mitigate or prevent muscle-volume atrophy on the disused side.

LIMITATIONS AND FUTURE DIRECTIONS

This study has limitations. The included literature is publicly available, omitting theses, possibly introducing publication bias. All participants were healthy, which limits generalization to those with major or chronic diseases. The focus on adults aged 18 to 30 years may not represent muscle adaptability in an older population. Cross-education induced by BFR is intricate, influencing body adaptations differently. Future research including robust randomized controlled trials is needed for comprehensive investigation.

Currently, no clear standard definition is available for the pressure-intensity limit of BFR. Variation in pressure among patients in the literature hinders the establishment of an optimal range. In addition, BFR variables, including automatic pressure regulation, occlusion time, deflation during rest, and methods for calculating total limb occlusion pressure, require ongoing exploration. Blood flow restriction training offers advantages through neural mechanisms, enhancing motor-unit recruitment and facilitating muscle hypertrophy and strength gains. However, its direct effect on muscle strength and quality is limited, potentially leading to slower progress after initial gains. Future research should be done to investigate CE and BFR mechanisms to enhance theoretical understanding and clinical efficacy in rehabilitation populations.

CONCLUSIONS

Our meta-analysis showed that BFR can stimulate CE of muscle strength, yet confirmation is pending regarding its effect on muscle volume. Reduced exercise intensity during BFR may enhance neural activation. Coupled with neural mechanism–based training, CE rehabilitation training holds distinctive exploratory value for patients with neurological disorders.