The most common method for increasing both muscle mass and strength is through the performance of high-intensity resistance exercise, where the American College of Sports Medicine typically recommends that resistance exercise training with loads exceeding 70% of maximal strength be used to induce optimal muscle hypertrophy. These recommendations are based on evidence that has accumulated over the past three decades, indicating that compensatory muscle growth results from mechanical loading of the muscle tissue and occurs in a fasting state and without insulin signaling. Therefore, tension development through either passive or active techniques by itself facilitates protein synthesis and is typically considered a fundamental determinate of skeletal muscle mass (10,13).
Increasing evidence suggests that hypertrophy also can be induced with low-intensity exercise performed under blood flow restricted (BFR) (ischemic) conditions (1,21,29). The observation that BFR exercise at low mechanical loading causes muscle growth seemingly opposes traditionally based programs. Although many questions remain regarding the efficacy, safety, and mechanisms of action of BFR exercise training, scientists are beginning to develop a better understanding of the model. This review aims to present the latest findings regarding BFR exercise and discuss the potential mechanisms of action that seem to be discordant with traditionally based theories of muscle hypertrophy.
MECHANICS OF BLOOD FLOW RESTRICTED EXERCISE
The concept of exercise training with BFR has been around for nearly 40 yr and was popularized in Japan by Yoshiaki Sato in the mid-1980s. Today, Sato has commercialized this training method in Japan (known as KAATSU training), where it is now relatively common. Although there is no universal way in which the training is used, it uses a relatively simple approach that generally involves placing a narrow compressive cuff around an appendicular limb, which is inflated during exercise (Fig. 1). The compressive pressure varies between studies, but typically, the cuff is inflated to a pressure greater than brachial diastolic blood pressure (BP) and upward of pressures exceeding systolic BP. Although it is common for the occlusive pressure to be above brachial systolic BP, it should be noted that the compressive pressure experienced at the artery is generally attenuated because there is a disassociation between tourniquet pressure and underlying soft tissue pressure, especially in the lower extremities (26). As such, the cuff pressure occludes venous return and causes arterial blood flow to become turbulent, and a reduction in blood velocity is seen distal of the cuff. With respect to knee extension exercise at an intensity of approximately 20%-30% 1-repetition maximum strength (1-RM), it is our experience that during BFR exercise with an occlusive pressure 30%-50% above brachial systolic BP, most subjects reach volitional task failure within 30-50 repetitions at a cadence of 2 s for the shortening action and 2 s for the lengthening action. One common feature of most BFR protocols, which may play an important mechanistic role, is that the compressive cuff remains inflated throughout the exercise session, including the rest period. As such, during subsequent sets, the number of repetitions that can be performed is substantially reduced by approximately 30%-50%.
MUSCLE ADAPTATION WITH BLOOD FLOW RESTRICTED EXERCISE
Resistance exercise-induced muscle growth involves a complex array of signaling events with a common denominator typically involving high mechanical loading. For example, Campos and colleagues (4) reported that 8 wk of resistance exercise training resulted in skeletal muscle fiber hypertrophy in individuals performing high-load resistance exercise training, whereas no significant increase was observed for subjects performing low-load training. However, in 2000, Takarada and colleagues (29) published the seminal report that 16 wk of low-intensity elbow flexor resistance training performed with BFR significantly increased muscle mass and voluntary strength comparable to that observed with high-intensity training without BFR (80% 1-RM) and more than an identical low-intensity protocol without BFR (Fig. 2). Similar observations regarding efficacy have been made by others, including reports that, as little as 3 wk of treadmill walk training performed with intermittent BFR results in a 6%-8% increase in quadriceps and hamstring muscle cross-sectional area (CSA) along with a 7%-8% increase in leg press and leg curl 1-RM strength (1). Whereas the majority of published studies to date have been conducted in healthy populations, Ohta and colleagues (21) evaluated the effect of low-intensity BFR exercise for ameliorating the loss of muscle mass and strength after anterior cruciate ligament reconstruction. Here, a group of patients performing rehabilitation exercises without BFR exhibited approximately 8% less quadriceps CSA and approximately 35% less knee extension strength in their injured limb in comparison to their healthy limb, whereas a group performing rehabilitation exercises with BFR exhibited a similar amount of muscle mass for both limbs and exhibited only approximately 15% less strength in their injured limb.
Although it is tempting to dismiss the observed hypertrophy associated with BFR exercise as a side effect of exercise-induced fluid shifts (i.e., edema), this seems highly unlikely based on the concomitant increase in muscle strength. Thus, although the application of BFR exercise for promotion of muscle hypertrophy and function is in its infancy, the early data challenges the existing paradigm for inducing muscle growth through high-intensity resistance exercise. These aforementioned studies also have led scientists in the field of muscle biology to appreciate the role that blood flow, or the lack thereof, has on modulating growth of adult skeletal muscle, and these recent findings suggest that a pathway for compensatory muscle growth may be mediated by muscle metabolism, byproducts of metabolism, reactive oxygen species (ROS), or another pathway independent of mechanotransduction that will be described in subsequent paragraphs.
INFLUENCE OF ISCHEMIA ON MUSCLE
One of the most fundamental features of any healthy cell is a high adenosine triphosphate (ATP)-to-adenosine diphosphate (ADP) ratio. Almost all of the energy-requiring processes in cells are due to the hydrolysis of one or more acid anhydride bonds in ATP to yield ADP or adenosine monophosphate (AMP). Low oxygen and pH levels have a dramatic influence on ATP resphosphorylation, hypoxia-induced reactive oxygen species, and regulation of cell energy-sensing pathways. This article is not intended to review the abundant research on the effects of ischemia on skeletal muscle metabolism; however, a brief summary is warranted to gain an appreciation of the environmental milieu created by BFR exercise.
Hypoxia induces dramatic changes in muscle metabolism that directly affect force production (2). For example, the relationship between tension development and energetic state at varying stimulation intensities is modified by tissue oxygenation levels (Fig. 3). Under normoxic conditions, stimulation causes a rise in tension with a parallel decrease in energy state. However, moderate hypoxia causes a slight decrease in tension and a large decrease in energetic state. With additional stimulation, the tissue is capable of producing tension in the range of normoxic conditions, and a dramatic price is paid with respect to the energetic state. This illustration (Fig. 3), derived from in situ preparations of dog muscle, demonstrates that low oxygen (O2) availability influences work output of muscle. As follows, ATP production is closely linked with ATP demand, and because ATP demand is reduced at low O2 levels, the energetic state of the cell falls, and ATP turnover is reduced. In fact, BFR has a dramatic effect on levels of O2 depletion from muscle tissue during elbow flexion exercise at 20% of maximal strength (Fig. 4). As such, BFR exercise results in longer-duration O2 depletion in muscle tissue. These relationships have important implications for understanding potential mechanisms of the BFR exercise model, with the end result being a shift toward anaerobic metabolism, as indicated by BFR exercise studies reporting an increase in systemic blood lactate levels and decreased blood pH levels (1,8).
When the rate of ATP breakdown exceeds ATP rephosphorylation, the ADP/ATP ratio rises, and the adenylate kinase reaction begins generating AMP, which is the key regulator of AMP-activated protein kinase (AMPK). AMPK is generally thought to be an energy sensor that allocates resources toward immediate demand for maintaining ATP production that include glycolysis, fatty oxidation, mitochondria biogenesis, and glycogen storage (11). In fact, chronic BFR exercise training has been shown to increase muscle glycogen content (3), and recent evidence supports that AMPK intrinsically controls glycogen storage, supporting a connection between BFR exercise and AMPK regulation (11), although there are no direct reports demonstrating its modulation with BFR exercise.
Another likely effect of BFR exercise relates to redox balance because hypoxia is emerging as a potential source for ROS production (5) especially under conditions involving low blood flow, intermittent ischemia, and reoxygenation. These conditions produce oscillations in electron sources causing redox disequilibrium, and the constant production of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) from glucose substrate metabolism coupled with O2 insufficiency in the mitochondria makes electrons more available for ROS formation. This association is powerful because inhibition of NADH completely blocks ROS production. With respect to the physiological implications, ROS are heavily involved in cell signaling and may cause muscle damage and delayed-onset muscle soreness (5), which could be involved in the muscle regeneration and adaptation process. However, at present, little is known about how these aforementioned metabolic factors play a role in regulating the muscle growth program that has traditionally been dominated by hormonal and mechanical pathways. In the next section, we will review the current literature on the mechanisms of muscle growth regulation associated with low-intensity BFR exercise.
MECHANISMS OF ACTION OF BLOOD FLOW RESTRICTED EXERCISE
The mechanisms underlying the hypertrophic response observed with BFR exercise training are not known, although they are likely to rise from a systemic and/or local response pathway. Therefore, we will present these data within the confines of these two divisions that are illustratively combined in the conceptual model presented in Figure 1. Several studies have been undertaken to gain a more basic understanding of the alterations in the molecular control of muscle growth associated with BFR exercise. Although some of these findings are discussed below, we should state that the mechanisms of muscle protein synthesis and degradation, satellite cell regulation, and concepts regarding energy sensing are very large and an evolving topic, far beyond the scope of this review.
The mechanism with the most empirical evidence is found in the endocrine responses seen with BFR exercise. There are numerous studies reporting that an acute bout of low-intensity BFR exercise increases serum growth hormone (GH) in young adults (22,23,28). For example, we have observed that five sets of knee extension resistance exercise at 20% of maximal isometric strength with a thigh occlusion pressure of 280 mm Hg results in an acute ninefold increase in serum GH (22) (Fig. 5). Additionally, low-intensity BFR exercise induces a fourfold increase in serum GH, which was significantly more than that observed for higher-intensity (70% of maximal strength) exercise without restriction; however, there was no effect on total testosterone, free testosterone, or cortisol (23). GH is known to increase both muscle- and liver-specific insulin-like growth factor-1 (IGF-1) production, which has been shown to have potent anabolic effects by activating satellite cells and stimulating pathways for protein synthesis, resulting in myofiber hypertrophy (12). With regard to BFR exercise, there seems to be a disconnection in this pathway as IGF-1 levels are unchanged (1,8). However, because GH has recently been suggested to directly facilitate cell fusion, an essential process for muscle growth, it may act independently of IGF-1 upregulation (14).
Although low-intensity BFR exercise results in an acute increase in serum GH concentrations, the associated stimulus for GH secretion is not known. One hypothesis is that BFR exercise results in greater stimulation of chemosensitive sensory nerves arising from the active musculature (namely class III and IV afferents). The rationale for this hypothesis is that the compressive cuff restricts arterial inflow, resulting in hypoxia and greater metabolic acidosis, while concomitantly blocking venous outflow resulting in continual stimulation of the afferents even during periods of rest between respective exercise bouts. Lactate has been suggested to play a critical role in regulating the exercise-induced GH release. This assertion is supported by the recent observation that individuals who lack the glycolytic enzyme myophosphorylase (McArdle disease), and thus do not increase their blood lactate during exercise, display a blunted GH response (9). Additionally, stimulation of the muscle spindle afferents via vibration increases biologically active GH in the plasma by 94%, suggesting a muscle afferent - pituitary axis link (18). Thus, although much of this argument is circumstantial, one potential mechanism of BFR exercise is that the local metabolic changes increase muscle afferent activity that feeds forward to modulate the GH response.
The strongest justification for a BFR exercise-induced systemic endocrine-mediated mechanism is based on the observation that 10 wk of low-intensity elbow flexion resistance training without BFR actually increased muscular size and strength when it was combined with low-intensity knee extension resistance exercise with BFR, indicating a "cross-transfer" effect for growth of other skeletal muscles (17). However, there are studies suggesting that BFR, in the absence of exercise (ischemia alone), attenuates atrophy after prolonged periods of disuse (6) (which does not increase GH; Fig. 5), which suggests that local mechanism(s) may be involved in determining the muscle adaptation associated with BFR.
Two recent reports have begun to uncover the underlying mechanisms leading to hypertrophy after BFR exercise. The first report by Fujita and coworkers (8) found that four sets of BFR knee extension resistance exercise resulted in a 46% increase in mixed muscle fractional synthetic rate, a measure of amino acid synthesis into protein, 3 h after exercise. Upstream phosphorylation of ribosomal S6 kinase-1, a regulator of messenger RNA translation initiation, showed a threefold greater increase than control exercise without blood flow restriction. Additionally, there was a reduced phosphorylation of eukaryotic translation elongation factor 2 after BFR exercise that is known to promote protein synthesis; however, this decrease was similar to that observed in the control exercise condition. Although protein Kinase B (Akt) and the mammalian target of rapamycin, which lie upstream, were unchanged in both conditions, it is possible that they were triggered transiently in the 3-h lapse between muscle biopsies. This same group of researchers has also reported changes in genes commonly expressed in association with skeletal muscle remodeling (7). They observed that markers of satellite cell activity (p21 and MyoD) and signals of protein turnover (MuRF1) were upregulated, whereas myostatin (an inhibitor of myocyte growth) was downregulated after BFR exercise. However, these changes were not different than those observed after exercise performed at the same intensity without BFR. This suggests that BFR did not differentially augment the transcription program in comparison to that of low-intensity exercise alone. However, because gene expression programs are transiently altered, the optimal window to detect gene expression may have fallen short, and thus, further data are needed to confirm these findings.
To gain a deeper understanding of potential mechanisms of BFR, Kawada and Ishii (15) attempted to develop an animal model of BFR by crush-occluding hind limb venous vasculature of rats. Fourteen days of venous occlusion resulted in increased muscle glycogen, lactate, and protein concentration, with the net effect being a 34% increase in muscle CSA without change in IGF-1 gene expression. In support of the increased muscle mass, protein levels of heat shock protein-72 (HSPs), and muscle-bound nitric oxide synthase-1 (NOS) were elevated along with a decrease in myostatin. HSP are widely recognized as playing a significant role in protein formation, are often found in conjunction with compensatory skeletal muscle hypertrophy, and are involved in cellular protection pathways as they reduce ischemia-induced damage of cardiac muscle perhaps by reducing apoptosis (30). Similarly, NOS, an enzyme most known for catalyzing NO production in myocytes and endothelial cells, also exerts a protective effect to cardiac muscle ischemia-induced damage (30) and has also been suggested to regulate contractile gene expression of contractile proteins (actin and slow myosin heavy chain) during overload (25). Collectively, these observations suggest that many properties of the muscle are altered when venous return is compromised, and they support the notion that downregulation of myostatin altered gene expression control, and increased mediators that aid protein formation may be involved in fiber growth due to BFR exercise. Although these data offer some insight into the mechanistic pathways, the validity of the model to BFR exercise must be questioned because of the imposition of complete and continuous venous occlusion as opposed to the short-duration temporal aspects of humans performing BFR exercise.
It should be noted that mechanical loading also occurs with BFR exercise, and thus, mechanotransduction pathways may remain intact. Moreover, higher mechanical loading per active muscle fiber could occur as the ischemic environment results in premature fiber fatigue of traditional oxidative fibers (type I) that are primarily recruited during low-intensity exercise resulting in the recruitment of glycolytic fibers, thus placing additional force on the fibers available. However, support for this pathway is limited based on two observations: 1) electromyographic activity during BFR exercise, although somewhat higher than that required for low-intensity exercise without restriction, is still substantially less than that involved in higher-intensity exercise (Fig. 6); and 2) BFR in the absence of exercise (ischemia alone) attenuates atrophy after prolonged periods of disuse (6).
The aforementioned discussion regarding factors in the regulation of muscle adaptation induced by BFR exercise is incomplete at this time. At the present, it is not clear whether hypertrophy is due to systemic hormones that stimulate the cascade of events leading to protein synthesis and satellite cell proliferation or if local muscle metabolism modulates protein formation pathways. Because genes that locally regulate hypertrophy through satellite cell activation (i.e., p21, MyoD, myogenin, and myostatin) (7) are unaltered by BFR exercise when compared with control exercise, the preponderance of evidence support the activation of protein synthesis through GH/IGF-1 signaling. Further research is needed to evaluate the contribution of these possible mechanisms, and others, in mediating the growth response seen with BFR exercise.
The development of a low-mechanical strain intervention to increase muscle function has considerable clinical significance because there are many conditions where traditional high mechanical loading paradigms for muscle adaptation cannot be used. For example, in injured and postsurgical patients with compromised musculotendinous integrity, high mechanical loading of a joint or muscle is frequently contraindicated. In addition, neurological conditions that result in the inability to voluntarily activate a muscle completely, such as cerebral palsy, make the achievement of high muscular tension through voluntary contractions difficult and at times impossible.
Despite mounting evidence for the general efficacy of low-intensity BFR exercise, there has been little implementation of the modality in exercise and rehabilitation medical settings in the United States. We believe that this hesitation is justified because, to date, there have been no clinical trials on the relative safety of BFR exercise, particularly in populations with health risks. As stated before, in recent years, this exercise modality has become popular in Japan, and Nakajima and colleagues (20) recently surveyed 105 facilities that use BFR exercise training in a variety of different populations to examine the observed incidence and occurrence of side effects of BFR exercise training. In total, more than 30,000 BFR exercise training sessions were reported, with the most frequent side effects being subcutaneous bruising at the location of the cuff (13.1%), numbness (1.3%), and lightheadedness (0.3%). Additionally, a few cases of venous thrombosis (0.06%) were reported, although this incidence rate seems to be lower than that reported for the general Asian population (∼0.2%-0.26%) (16). In general, based on the aforementioned side effects as well as theoretical reasoning, some of the primary concerns regarding BFR are those associated with training-induced alterations in the following: 1) adverse cardiovascular responses, 2) blood clotting and vascular function, and 3) nerve and muscle damage.
Based on the integrative systems involved in BFR exercise, one can easily surmise that there are many stressors placed on the cardiovascular system. As such, experimentally induced ischemia is a powerful research tool for studying endothelial function that commonly results in heightened heart rate and pressor responses. When compared with low-intensity control exercise, low-intensity BFR exercise causes an increase in heart rate and systolic and diastolic BP and a decrease in stroke volume because of compromised venous return (28). Preliminary data from our laboratory supports previous work and suggests that heart rate and systolic BP responses are similar when performing either high-control or low-intensity BFR knee extension exercise until failure (Fig. 7A). BFR exercise, however, amplified the peak diastolic BP over a longer period of recovery. Consequently, BFR exercise may have additional demands on the cardiovascular system not seen with the currently recommended free-flow high-intensity exercise.
It is our experience, through discussions with numerous clinicians and scientists, that the most common safety concern with respect to BFR exercise surrounds the potential for thrombolytic events. It is likely that these concerns exist based on the apparent impact of BFR exercise on some of the broad categories encompassed in Virchow triad. Virchow triad involves three common factors thought to contribute to venous thrombosis, which include the following: 1) alterations in normal blood flow, 2) injuries to the vascular endothelium, and 3) alterations in the constitution of blood (i.e., hypercoagulability). Thus, because this modality is based on altering normal blood flow, coupled with the observations that mechanical compression of vessels has been shown to induce structural damage in animals (24), it seems to be a reasonable theoretical concern. However, the preliminary findings suggest that BFR exercise training does not change blood clotting time or vascular function (Fig. 7B). These findings regarding the risk of blood coagulation are not overly surprising because vascular compression alone is a well-known stimulant of the fibrinolytic system without elevation of the coagulation cascade (27).
Extended periods of ischemia may be associated with nerve and/or muscle damage (19), yet very little is known with regard to the potential for BFR exercise to cause this type of harm. As stated before, numbness is an occasional side effect reported by subjects performing BFR exercise, and this may be due to pressure being applied to the peripheral nerve causing nerve conduction blockage. Numbness and acute nerve conduction alterations, however, do not result in any long-term maladaptations, as indicated by the extremely low incidence of nerve damage during surgical procedures performed in a bloodless field accomplished by applying a tourniquet cuff (incidence rate of 0.007%) (19). Additionally, preliminary data from the our laboratories suggests that 4 wk of lower-extremity BFR exercise does not alter nerve conduction (Fig. 7B).
Considering the limited data regarding the safety and clinical viability of BFR exercise, we must caution against the immediate clinical application of BFR exercise by medical professionals. Virtually all the work reviewed above was performed on young healthy populations, and it is possible that BFR exercise may have interactive risks in populations with comorbidities. Therefore, it is imperative that long-term safety and feasibility studies in vulnerable populations be performed before the use of this modality because it is possible that unknown and/or interactive risks have not been identified.
There are many unanswered questions regarding BFR exercise ranging from applied aspects of safety, efficacy, and indications to basic science issues related to its mechanistic underpinnings. Regarding the applied aspects of BFR exercise, the modality will need to undergo the same rigorous scrutiny as aerobic and resistance exercise with respect to safety and applicability in clinical environments. Scientific endeavors have now made exercise a critical component to improving and maintaining human health, but there are still many patient populations who cannot safely or effectively perform certain exercise regimens. As such, the first logical steps are to establish the viability of BFR exercise by continuing to build evidence demonstrating the efficacy; establishing the relative safety and modifications in risk factors in long-term studies; determining whether certain populations can tolerate the modality; evaluating optimal cuff pressures, sizes, and exercise modes and intensities; and identifying populations whereby BFR exercise is contraindicated.
There are several investigative directions that can be taken to pinpoint the potential regulators of muscle hypertrophy with low-intensity BFR exercise. For example, one reasonable approach would be to experimentally manipulate the effects of hypoxia, buildup of metabolic byproducts, and mechanical loading to tease out the respective contributors. In conjunction with close monitoring of tissue oxygenation and blood flow, changing tourniquet cuff pressures may allow researchers to study hypertrophy precursors in association with varying degrees of venous and arterial occlusion. Additionally, in conjunction with altering cuff pressure, exercise intensity may be modified, and the systemic and local factors can be studied alongside the experimental conditions to identify potential mechanisms. Lastly, the development of an animal model would be beneficial because it would allow for more invasive and definitive mechanistic studies to be conducted.
Hormonal and mechanical regulators for muscle hypertrophy have dominated the literature for the past half-century. New ways of inducing muscle growth by altering muscle metabolism and afferent feedback through BFR may help identify more efficient ways for initiating compensatory muscle growth. Whereas many questions remain unanswered on both the clinical and basic science aspects of BFR exercise, the modality is certainly intriguing because it seems to challenge traditional hypertrophic pathways that may be independent of current recommendations for high mechanical loading.
The NIA Claude D. Pepper Center P30AG028740 and a grant from the Institute on Aging at the University of Florida supported T.M. Manini's work on this topic. NASA training fellowship NGT-50446 and grants from the Ohio University Research Committee and the Ohio University College of Osteopathic Medicine supported B.C. Clark's work regarding this topic.
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