BFRT can be coupled with body weight exercise, elastic band resistance exercise, and traditional resistance exercise (21). BFR resistance training, which causes a combination of mechanical and metabolic loads, can prevent the loss of muscle mass and strength caused by increasing age (22).

BFR resistance exercise training is known as “kaatsu training,” which means “training with added pressure.” This method couples low training intensity [~20–50% 1 repetition maximum (RM)] with an external pressure cuff applied to the exercising limb (23), which differs from traditional high load resistance training. In addition, an important difference between high-load and BFRT is that high-load resistance exercise training enhances muscle strength through nervous system adaptation, which is in contrast with BFR exercise training, which increases muscle strength mainly through the mechanism of muscle hypertrophy (24).

BFRT is usually prescribed at low intensity. Because BFRT can efficiently attenuate severe muscle wasting and improve muscle mass and strength, which significantly improves the muscle condition in clinical practice, it is regarded as an effective method to treat sarcopenia (25). Extensive research has also shown that it might serve as a well-tolerated novel intervention that can improve muscle rehabilitation and regeneration to counteract sarcopenia (26).

In a previous report, exercise conducted with BFRT resulted in a significant improvement in the functional capacity of elderly women after 16 weeks (27, 28), demonstrating that BFR-associated lower intensity resistance training can serve as a more effective alternative to low-load resistance training alone and a surrogate for traditional high intensity resistance training. Thus, BFRT can be used as a progressive clinical rehabilitation tool in the process of returning to heavy-load exercise.

Aerobic training can improve aerobic fitness and arterial function, but it is insufficient to improve muscle mass and strength to counteract the loss of muscle strength that accompanies advancing age (29). However, BFR with an external pressure cuff applied to the upper legs can be combined with aerobic exercise training, such as low-intensity walking or cycling (~20–40% of maximal oxygen consumption). BFR aerobic exercise can not only improve aerobic fitness at a lower intensity but also increase muscle strength and muscle mass (30). Thus, this method can also serve as a novel way of improving muscle ability and can even be applied in the management of sarcopenia.

Other studies have reported that low-intensity BFR walking increases functional ability in older adults, which may be associated with improvements in the overall quality of life and better treatment of sarcopenia (25). Bench-step aerobic exercise with elastic bands is also used in relevant studies to further investigate the mechanism of BFR aerobic training, and significant increases in the vastus lateralis and rectus femoris cross sectional area were observed (25). Overall, the effectiveness of BFRT, when accounting for other variables, requires further exploration.

Skeletal muscle is highly irrigated by blood vessels (40). In skeletal muscle, endomysial capillaries run parallel to the myofibers (40). The function of muscle microcirculation is to improve muscle contraction that depends on energy substrates (40). The microvasculature can also impact myocyte amino acid availability (11).

Through increasing vascular stress, BFRT triggers hemodynamic responses and thus alters the circulating environment of skeletal muscle. BFRT sessions induced higher systolic and diastolic blood pressure increments (26, 41). It appears that the partial pressure applied to tissue might change the vascular resistance or alter the blood flow output to increase blood pressure. Additionally, ischemic reperfusion following BFRT can induce reactive hyperemic blood flow and increase microvascular filtration capacity (42) in such a way that endothelium-dependent vasodilation during reactive hyperemia is improved (43). A long duration of muscle O₂ depletion (44) can trigger arteriolar remodeling (45) and even induce angiogenesis through vascular endothelial growth factor (VEGF) (45). The recruited tortuous capillaries contacting myocytes are the nutritive routes essential for muscle perfusion (45). Because BFRT leads to the recruitment of muscle microvasculature (8), reactive hyperemia and hence nutritive flow to the muscle afterward, such as an increase in blood flow and amino acid utilization, can stimulate protein synthesis in muscle directly (46), which can in turn activate the anabolic stimuli of cells (8). All of the mechanisms mentioned above appear to offer a chance to improve the condition of skeletal muscle and thus have beneficial consequences in treating sarcopenia.

However, the mechanisms at the micro level of BFRT on vascular reactivity remain unclear. For example, BFRT does not increase peak forearm blood flow (FBF) or forearm vascular conductance (FVC) in older adults (47), while BFRT did increase peak FVC in the young group; a change in FVC can demonstrate an increased vascular size and increased number of capillaries (42). These results suggest that intriguing mechanisms underlie the observed alternations and open new possibilities for the further exploration of possible reaction channels.

Additionally, because external pressure restricts blood flow, muscle metabolites accumulate in muscle tissue, and these substances can affect muscle responsiveness during BFRT (30) and initiate muscle protein transcription and translation (48). Neuromotor adaptations, combined with tendon and bone adaptations, are also achieved through metabolite accumulation (48, 49). Stimulation of afferent nerves III and IV has been reported, which could in turn lead to the recruitment of type II muscle fibers (50). The molecules induced by metabolite accumulation can include growth hormone (GH), insulin-like growth factor-1 (IGF1), GH-releasing hormone, testosterone (T), and other anabolic- and catabolic-related factors (30). Under pressure conditions, the swelling effect and the secretion of growth hormone and serum testosterone were higher (46).

Hormone imbalances are often associated with sarcopenia (11). A previous study reported that the accumulation of metabolic byproducts leads to the increased secretion of growth hormone (GH) and GH-releasing hormone (51). This effect has been demonstrated, to a large extent, with circulating growth hormone concentrations 290 times higher than baseline reported after acute BFR exercise (52). The increase in growth hormone (GH) and GH-releasing hormone corresponded with the increase in IGF-1. The GH-IGF-1 axis has long been considered a beneficial factor for skeletal muscle growth, while a decrease in the production of IGF-1 is associated with sarcopenia (2). The GH/IGF-1 axis activates the phosphatidylinositol 3 kinase/protein kinase B (AKT) pathway, which increases muscle protein synthesis (MPS) by activating the mammalian target of rapamycin (mTOR) signaling pathway and decreases muscle protein breakdown (MPB) by inactivation of the Forkhead Box O (FOXO) transcription factor (53, 54). Considering these channels, BFRT can greatly improve muscle conditions in patients with sarcopenia. However, some researchers have reported the opposite result. During BFRT and at 10–30 min postexercise, an increase in IGF-1 was observed, while an acute bout of BFRT showed a stagnant level of IGF-1 concentration (23, 55, 56). It is thereby hypothesized that hemoconcentration as a result of plasma volume (PV) changes might be the real cause of the increased level of IGF-1. Therefore, the overall relationship between BFR resistance exercise and the GH-IGF1 axis remains controversial and requires further exploration.

Testosterone (T) is a male hormone that is a steroid hormone and is likely to offset the decline in muscle mass in sarcopenia. Increased testosterone in the BFRT can increase muscle mass and function through its stimulating effect on IGF-1 protein synthesis (57). Only a few reports have observed changes in testosterone, in total or free, following BFR resistance exercise. Madarame et al. reported a postexercise elevation in the total T following BFRT and flexion (55). Thus, the real role that T plays needs further investigation.

Therefore, it is reasonable to conclude that BFRT plays a beneficial role in the management of sarcopenia regarding the microenvironment of skeletal muscle. BFRT helps to improve muscle condition and provide better treatment of sarcopenia. However, more work is required to determine what specific factors play a role and what their contributions are in BFRT.

Hypoxia responses are key elements of BFRT. Energetic and hypoxic stress regulates the muscle growth response in BFRT. The combination of local muscle hypoxia enhances glycolytic cell metabolism, triggers a synthetic hormonal response (57), and activates cellular signaling cascades to increase protein synthesis and inhibit protein degradation (44).

A partially hypoxic environment enhances anaerobic metabolism, increasing muscle biopsy lactate and blood lactate and hence decreasing the pH of muscle cells (30). Usually, lactic acid is produced by fast muscle and transported to the blood by the lactic acid transport carrier MCT4 on the cell membrane (58). Then, it is transported to the vicinity of slow muscle fibers through blood circulation (23, 58). Under pressure, the limited venous blood flow makes it difficult to transport and decompose lactic acid produced by muscles, both during exercise and between exercises (23, 58). This fact can lead to changes in the phenotypes of glycolytic fibers, thus helping to combat sarcopenia. Lactic acid accumulation can also cause muscle cell swelling (59). This effect, in turn, can reduce proteolysis and activation of the mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways (60, 61). Activation of these signaling pathways, especially mTOR, enhances muscle protein synthesis and hence leads to muscle hypertrophy (44). Ultimately, this method provides a new target for curing sarcopenia, which is a beneficial factor in BFRT. A 20% 1-repetition maximum-intensity knee extension exercise with kaatsu can enhance the Akt/mTOR signaling pathway and thigh muscle protein synthesis in young men (62). In addition, in the MAKP pathway, ERK1/2 can phosphorylate Mnk1, which in turn can activate the eIF4E translation initiation factor (46). Presently, ERK1/2 and Mnk1 phosphorylation were reported to increase in BFRT, suggesting that simultaneous activation of mTOR and MAPK signaling pathways may be required for maximum muscle protein synthesis in response to BFRT (63). More studies on different subjects are needed to further investigate the relative mechanisms of the signaling pathways.

Mitochondrial dysfunction in sarcopenia can induce the loss of skeletal muscle mass and neuromuscular junction (64). Anaerobic metabolism can increase mitochondrial function (65), which can preserve and improve the proliferation of muscle cells in sarcopenia. Transient fluxes of several substances, metabolites and nucleotides in skeletal muscle during BFRT may trigger an increase in stimulating transcriptional pathways and signal transduction cascades that ultimately regulate mitochondrial biogenesis programs (66). Sarcopenia is reportedly accompanied by changes in cytoplasmic calcium homeostasis through alterations in dihydropyridine receptors and calcium pump proteins and an increase in cytoplasmic free calcium (67). Sarcoplasmic reticulum Ca²⁺ decreases can be associated with increased cytosolic Ca²⁺, which leads to a decline in muscle strength and quality (67). An increase in mitochondrial production, as important players in buffering cytosolic Ca²⁺ leaked from the sarcoplasmic reticulum, can help cytosolic calcium regulation and buffer its concentration and then enhance both muscle function and strength (67). Training in hypoxia has also shown an angiogenic response in young animals (68), such as an increase in skeletal muscle capillary density (69). From the reports, the pathways in muscle tissues under hypoxia undergo crosstalk with the hormones in the blood vessels, which form an integral system in response to BFRT in sarcopenia.

Heat shock protein is induced by ischemia, hypoxia, and free radicals (70). Increasing HSP72 attenuates atrophy and may play a role in muscle hypertrophy in BFRT (71). However, other researchers have concluded that HSPs do not participate in BFRT as no improvement in HSPs was observed (72, 73). The difference in study subjects may have led to controversial results. Thus, the role of HSPs in BFRT still needs to be verified.

It was previously proposed that hypoxic stress increases the expression of hypoxia-inducible factor (HIF-1) and REDD1, which can inhibit the mTOR pathway (74, 75). However, there are no reports of significant changes in HIF-1 and REDD1 in BFRT (76). Additionally, protein carbonyls and blood glutathione, which are indicators of oxidative stress, were not increased in low-intensity (30% 1RM) BFRT but increased in moderate-resistance exercise (up to 70% 1RM) (77). Therefore, the hypoxia responses and the concrete pathways activated in BFRT need further investigation.

In conclusion, under hypoxia, BFRT activates muscle fiber cells and SGs through several pathways and enhances muscle mass and strength, leading to muscle hypertrophy, which ultimately provides a beneficial condition for managing sarcopenia. During this process, mitochondria play an important role. However, the exact functions of the pathways need verification. More pathways concerning hypoxia might be discovered in the future.

On a muscle-specific level, sarcopenia is characterized by a decline in the number of type II muscle fibers and a loss of SGs in type II fibers. A previous study demonstrated that alpha-motor neuron loss can be largely responsible for the loss of muscle mass (78). From this aspect, BFRT can mitigate the effect of sarcopenia through the recruitment of muscle fiber and SGs.

The ESWGOP proposed several standards for an effective method of exercise in treating sarcopenia, which include “to be best suited and most effective for older people,” “enables older people to take more habitual physical activity,” and “alternatives to traditional exercise programs for people who have marked physical limitations” (1, 3). BFRT can fit into such standards.

BFRT can be conducted with a low exercise training load and shows equal or even superior results when compared to traditional high-intensity training. According to the report, two daily BFR sessions combined with low-load resistance training produced significant muscle strength gain and increased muscle mass in only 6 days (93, 94). To achieve the same effect, traditional resistance training requires a longer training duration and a higher training load or volume (95, 96). BFRT can significantly increase thigh muscle size and arterial stiffness (97, 98). In this sense, BFRT is a more effective way to improve muscle strength and physical performance and an alternative to traditional exercise programs.

Sarcopenia is known to be associated with comorbidities, including several underlying diseases (2). BFRT has executable functionality in older individuals with minimal risk of damage (23, 30, 64, 99), and thus, it is suitable for older individuals and those with sarcopenia along with underlying diseases who have marked physical limitations. Patients with sarcopenia who often underwent BFR combined with low-load resistance training did not experience sustained declines in muscle function, exaggerated levels of muscle soreness or increased muscle injury (20, 100, 101), which is beneficial for clinical rehabilitation and elderly populations unsuitable for high loads. Because of its relative ease of implementation and its low load, BFRT enables older individuals to perform more habitual physical activity, which is essential in treating sarcopenia and significantly improves muscle strength, muscle mass and physical performance.

BFRT can increase fibrinolytic activity, thus reducing the risk for blood coagulation (30, 43). Clark et al. observed that tissue plasminogen activator, a fibrinolytic protein, immediately increased following BFRT (27). The accompanying benefits brought by BFRT can offer new insights into treating comorbidities such as cardiometabolic risk factors and diabetes.

Importantly, BFR is accompanied by a “cross-transfer” effect in which endogenous anabolic hormones of blood flow-restricted muscles were observed in non-restricted muscles (82, 102). This finding suggests that BFR can also influence the muscle when it is not under the application of pressure.

BFR has its limitations. The application of BFR exercise is limited to peripheral muscle groups; thus, core, back, and neck muscles cannot be specifically targeted using this methodology (30, 103).

The other disadvantage of BFRT is that it can lead to a sense of discomfort and even damage to muscle. Higher perceptual ratings and pain during the remaining intervals of sets can also limit the application of BFRT (30, 104). Higher levels of muscle soreness and perceived tiredness have been reported during or following BFRT compared to traditional training (30, 57, 105). The pressure applied to the blood vessel during BFRT is likely the prime cause of the discomfort (98, 106). Myocellular muscle damage and even rhabdomyolysis can occur in response to unaccustomed or excessive BFRT (30, 107). In addition, acute cardiovascular responses to BFRT are also important to consider (30, 108).

Microvascular dysfunction may be the result of reperfusion during blood flow recovery after a period of limitation or ischemia. During reperfusion, there is an acute release of inflammatory molecules and reactive oxides that impair microvascular function. In addition, when blood flow is restored, NO bioavailability (a vasodilator) is reduced, which leads to impaired arterial vasodilation and an increase in pure pressure (43, 107). Repeated reperfusion injury can influence endothelial function. Increased sarcolemma permeability is reported following BFRT, which can be caused by cell damage from the production of reactive oxygen species (30, 109).

BFRT is accompanied by other adverse side effects, such as dizziness, subcutaneous or petechial hemorrhage, drowsiness, numbness, nausea, and itchiness (98, 110). Therefore, we should pay more attention to the safety of BFRT in clinical applications. The advantages and disadvantages reported in sarcopenia, which are mentioned above, are shown in Table 1.