The anabolic benefits of venous blood flow restriction training may be induced by muscle cell swelling
Introduction
The American College of Sports Medicine (ACSM) recommends lifting a weight of at least 70% of one’s concentric one repetition maximum (1-RM) to achieve muscular hypertrophy as it is believed that anything below this intensity does not produce significant muscle growth [1]. However, venous blood flow restriction (VBFR) combined with low intensity exercise (20–30% concentric 1-RM) has been observed to result in skeletal muscle hypertrophy [2], [3], [4], [5], [6], increased strength [2], [3], [4], [5], [6], [7], [8], [9], and increased endurance [4], [7]. Additionally, the application of VBFR alone, without exercise, has been shown to attenuate muscle atrophy [10]. VBFR appears to be safe and poses no greater risk than traditional high intensity resistance exercise with respect to the cardiovascular system, muscle damage, oxidative stress, and nerve conduction velocity [11]. VBFR involves applying a wrapping device, typically a pneumatic restriction cuff proximal to the muscle being trained [12].
The mechanisms behind the benefits seen with VBFR have yet to be established, but have traditionally been thought to occur from the decreased oxygen available to the muscle and the accumulation of metabolites [13]. Both reduced oxygen and metabolic accumulation can increase high threshold fiber recruitment, mechanistically speaking, through the stimulation of groups III and IV afferents which may cause inhibition of the alpha motorneuron supplying slow twitch fibers, resulting in an increased fast twitch fiber recruitment to maintain force and protect against conduction failure [14]. Furthermore, increases in metabolites during exercise are thought to contribute to driving the pressor reflex which increases both heart rate and blood pressure [15]. It has been postulated that increases in metabolites may also facilitate the increase in growth hormone observed following VBFR exercise [16]. Although increases in systemic hormones may not play a large role in the anabolic response [17], it has nevertheless been hypothesized as a primary mechanism. In addition, the VBFR exercise induced increases in heat shock proteins (HSP) and neuronal nitric oxide synthase activity have also been proposed to play a role in muscle adaptations to VBFR [13].
Although all of these proposed mechanisms appear valid and are likely associated with VBFR combined with resistance exercise, there are certain situations in which benefits are observed without a large accumulation of metabolites and/or large increases in fiber type recruitment. Furthermore, HSPs and neuronal nitric oxide synthase have only been mechanistically demonstrated in animal models following chronic blood flow restriction [18], which may not correspond to the conditions observed with transient VBFR in humans.
Kubota et al. [10] reported that applying VBFR to a non-exercising limb, prevented disuse muscular weakness, moreover, they found no increases in serum growth hormone from VBFR, despite the maintenance of both strength and leg size. Since exercise was not performed in this study, it is doubtful that the accumulation of metabolites facilitated any of the observed benefits reported from VBFR.
VBFR in combination with walking exercise also results in minimal increases in metabolites. Despite this lack of metabolic accumulation, this mode of exercise results in substantial muscular adaptations. Abe et al. [2] observed significant increases in skeletal muscle hypertrophy and strength, despite growth hormone levels only increasing a small degree compared to previous studies using VBFR during resistance exercise. To illustrate, with low intensity walking [2], growth hormone peaked at 13 ng/ml while VBFR combined with knee extension resistance exercise increased growth hormone to 40 ng/ml [19]. Likewise, muscle size and strength increased in elderly subjects following 10 weeks of VBFR walk training without a significant increase in growth hormone (personal communication) [20]. If we accept that metabolic accumulation is what drives the hormonal response [13], then it becomes clear that metabolites produced from VBFR low intensity walking (unpublished observations) is much less than when combined with resistance exercise [21].
Other mechanism(s) may also contribute to the muscular benefits observed with VBFR exercise and particularly with VBFR alone. In order to provide one possible mechanistic explanation, we measured muscle size by ultrasound, in response to walking with and without VBFR. We found acute increases in muscle thickness (an index of muscle cross-sectional area) with VBFR walking but not walking without the application of VBFR. Furthermore, maximal voluntary contractions assessed following both conditions were not different (unpublished observations), suggesting that fatigue was not driving the hypertrophic effects seen with VBFR walking [2]. Coupled with previous findings that metabolic stress/hormones are not significantly elevated with VBFR walking, we hypothesized the acute increase in muscle size and decrease in plasma volume [22] were accompanied with changes in muscle cell volume, leading to the current hypothesis that muscle cell swelling may be the one consistent mechanism working throughout all studies.
Cell swelling induced changes in protein anabolism and catabolism is a theory that was first introduced by Haussinger et al. [23]. Cell swelling is able to inhibit catabolism, shifting the protein balance towards anabolism. For example, when insulin-induced hepatocyte cell swelling was prevented by inhibitors of Na+–H+ antiporter or Na+ K–2Cl cotransporter, the anabolic effect of insulin was also prevented, suggesting that much of the anabolic effect of insulin was due to increased cellular volume [24]. Besides inhibiting catabolism, human research indicates that cell swelling can also positively affect metabolism through the sparing of protein and promotion of lipolysis [25], [26]. It is currently speculative to the degree of parallel between a hepatocyte and muscle cell model, however muscle cell swelling may be the foundational mechanism by which the aforementioned mechanisms combine to produce a greater hypertrophic potential following VBFR resistance exercise.
Although mechanisms behind the potential anabolic effect of muscle cell swelling are not well understood, it is conceivable that the blood pooling induced by applying VBFR may be sufficient to cause shifts of intracellular and extracellular water balance, even without exercise. In mammalian cells, water passes across cell membranes by simple diffusion. VBFR may increase the intracellular to extracellular pressure gradient thereby increasing the water flux into the cell helping to drive that response, which without VBFR, is typically insufficient for sustained and rapid water fluxes required for active regulation of water homeostasis [27]. Another possible factor to consider is the reperfusion of blood flow to the muscle following VBFR. Research supports that the degree of hyperemia is related to the duration of restriction and that greater durations of blood flow restriction result in greater hyperemia [28]. The restoration of blood flow could provide the stimulus for forcing fluid into the muscle cell from the altered pressure gradients, and cellular channels may explain how the fluid shift from the extracellular to intracellular space occurs.
Aquaporins are a family of transmembrane water channel proteins that are widely distributed in various tissues throughout the human body which play an integral part in transcellular and transepithelial water movement [29], [30]. Aquaporin 4 (AQP4) is the major channel found in fast-twitch muscle fibers and appears to be involved in the rapid equilibration of osmotic gradients created from the intracellular accumulation of metabolites [27]. Although this metabolic accumulation is likely minute with VBFR walking or VBFR alone, it is hypothetically plausible that the hypoxic environment produced from the restriction of blood produces at least small increases of intracellular metabolites. As a result, this would cause an increased flow of water into the cell to equilibrate the osmotic gradient and may transiently increase muscle cell volume, subsequently activating the signaling cascades for growth. The increase of intracellular metabolites would be even greater when VBFR is combined with resistance exercise which would cause a greater movement of water from the circulation into the working muscle.
We hypothesize that exercise and/or VBFR results in an increased water content of the muscle cells, which induces a cascade of intracellular signaling to occur. Research on hepatocytes provides much of the information currently known on the role of cell swelling and subsequent signaling. Based on Haussinger’s hypothetical model for hepatocyte cell swelling [31], we speculate that during VBFR, muscle cell swelling is detected by an intrinsic volume sensor. The activation of this volume sensor may lead to a G-protein-medicated activation of a currently unidentified tyrosine kinase, which leads to an activation of the mammalian target of rapamycin (mTOR) and mitogen-activated protein-kinase (MAPK) pathways. The mechanism is thought to be related to activation of a G-protein and tyrosine kinase because research demonstrates that some of the metabolic responses to hepatocyte cell swelling are completely abolished by G-protein and tyrosine kinase inhibitors [31].
The mTOR pathway is believed to act as the master network regulating skeletal muscle growth [32]. When mTOR is activated, signals are sent which then act on downstream targets to increase muscle protein synthesis leading to skeletal muscle hypertrophy. Research has shown that cellular dehydration may be involved in down-regulating mTOR signaling [33]. If it is possible that the application of VBFR can transiently increase the influx of water into the muscle cell and thus mTOR signaling, then this may partially explain the attenuation of atrophy seen with VBFR without exercise [10].
The activation of MAPK has been shown to link cellular stress with an adaptive response in myocytes, modulating both growth and differentiation [34]. Three distinct MAPK signaling modules, extracellular signal-regulated kinases (ERK 1/2), p38 MAPK, and c-JUN NH2-terminal kinase (JNK), have been associated with the adaptation of skeletal muscle, particularly from exercise. JNK is the most responsive to mechanical tension and has been linked to a rapid rise in the mRNA of the transcription factors which modulate cell proliferation and DNA repair [35]. Interestingly, c-JUN mRNA, a downstream target of the JNK pathway, has been observed to increase 30 min after the onset of hepatic cell swelling [36], [37]. Also, expression of ERK 1/2, which are proteins associated with osmosensing [38], [39], are increased following VBFR exercise [40]. In addition to activating MAPK, VBFR exercise results in concurrent activation of the mTOR signaling pathway [40], suggesting that both mTOR and MAPK are needed to induce a maximal muscle protein synthetic response following resistance exercise (Fig. 1, Fig. 2).
Section snippets
Conclusions
In conclusion, previous literature demonstrates the importance of maintaining cell volume, due to its role in cell signaling [41]. With VBFR, this could be of primary importance for clinical populations who are unable to exercise with high loads or for those whom resistance training is contraindicated. The application of VBFR may be able to induce muscle cell swelling through a combination of blood pooling, accumulation of metabolites, and reactive hyperemia following the removal of VBFR which
Conflict of interest
None of the authors report any conflicts of interest.
Acknowledgment
This paper was not supported by funding from an outside source.
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