Review of literature
This review of literature begins with the importance of resistance training in athletic populations. The effects of resistance training on muscle strength and hypertrophy will be explained, in addition to the hormonal hypothesis and its application to resistance training. Then, the importance of resistance training combined with blood flow restriction (BFR) and/or in systemic hypoxia on muscle strength and hypertrophy will be discussed. Finally, the differences between BFR and resistance training in systemic hypoxia (RTH) methods and its importance to athletic populations will be detailed.
Importance of resistance training for athletes
Strength or resistance training in various athletic populations has been shown to improve the physical capacities of strength, power and speed . With the aim of improving these physical qualities, resistance training also has significant benefits for athletic populations to generate increases in muscle hypertrophy (skeletal muscle growth) and reduce the risk of injury . Given that that there is a strong correlation between muscle cross-sectional area (CSA) and muscular strength , it is necessary for athletes to consistently perform resistance training in an attempt to increase their muscle mass, which in turn can lead to performance improvements. There are various forms of resistance training programs that athletes currently undertake with the aim to enhancement performance through increases in muscular strength and hypertrophy . A summary of the effectiveness of resistance training programs to achieve a specific training outcome to improve athletic performance is outlined in Figure 1.
Effects of resistance exercise on muscle strength and hypertrophy
Proper resistance exercise prescription and manipulation of the acute training variables (e.g. intensity, volume, exercise selection and rest intervals) is necessary for maximising exercise-induced muscle hypertrophy . It is imperative to integrate three fundamental concepts of progression (e.g. variation, progressive overload and specificity) when designing a program in an attempt to maximise hypertrophic adaptations . For example, motor unit recruitment will increase with a progressive overload stimulus . The aforementioned training variables that may have a significant impact on the hypertrophic response will be further discussed.
Intensity also defined as load, has been suggested to be the most important exercise variable for stimulating muscle growth and has be shown to have a significant impact on muscle hypertrophy . Intensity is typically expressed as a percentage of 1RM and is associated with a number of repetitions that can be performed with a specified load. Repetitions can be further categorised in 3 basic ranges including; low (1-5 reps), moderate (6-12 reps), high (>15 reps) . The performance of resistance exercise in these repetition ranges will strain the neuromuscular system and target different energy systems in several ways, which may significantly impact the degree of the hypertrophic response .
The extent of muscular strength and hypertrophic gains following resistance training are universally thought to be dependent on the intensity of exercise, with an intensity of ‘65% 1RM considered to be sufficient to promote substantial muscular hypertrophy . As a result, the use of moderate to low repetition ranges has typically been proven to elicit greater increases in muscle hypertrophy compared to high repetitions . Although, there is a recent body of literature proposing that resistance exercise combined with BFR can promote significant increases in muscle hypertrophy with exercise intensities as low as 20% 1RM . While it still remains inconclusive as to whether the use of low, moderate or high repetitions to induce the greatest hypertrophic response, there is a prevailing body of evidence suggesting that resistance exercise at a moderate range (6-12 reps) is optimal for the production of muscle hypertrophy [12-14]. There are several factors that are associated with the use of moderate repetitions promoting the greatest anabolic response; these primarily include metabolic stress, increase fibre recruitment and systemic hormonal production. These factors will be further discussed in greater detail in this literature review.
Exercise volume can be defined as the product of total sets, repetitions and load complete in a training session. With respect to gains in muscle hypertrophy, multiple-set, higher-volume protocols have consistently proven to be far superior compared to lower-volume, single set protocols [15, 16]. While it is not entirely clear as to why higher-volume workloads is superior in promoting muscular hypertrophy, it is suggested that a combination of several factors such as greater total mechanical tension, metabolic stress and muscle damage are implicated . High-volume (body-building) type schemes, have demonstrated to produce significant glycolytic activity which has been shown to maximise the acute anabolic hormonal response to a greater extent than low-volume (strength based) schemes [17, 18]. The increase in metabolic stress has been associated with the augmentation of anabolic hormones such as growth hormone (GH) and testosterone, therefore increasing the potential for downstream cellular interactions to create a hypertrophic effect on muscle tissue .
There is evidence to support that the selection of exercise may play a role in maximising the hypertrophic response. Programs that primarily incorporate multi-joint exercises tend to recruit greater amounts of muscle mass, which has an impact on the anabolic hormonal response to resistance training [4, 20]. It has been demonstrated that the magnitude in the elevation of anabolic hormones post-exercise is associated with the degree of muscle mass involved, with multi-joint exercises producing greater increases in GH and testosterone compared to single-joint exercises [21, 22].
The rest periods is referred to the time taken between sets. Rest periods can be categorised into three basic ranges including; short (’30s), moderate (60-90s), and long (‘3min). The manipulation of these categories can have a diverse effect on the capacity of strength and build-up of metabolites, thus having an impact on muscular hypertrophy .
Long rest period between sets allow full recovery of strength, which facilitates the ability to train with maximum force . It has been demonstrated that when training with loads between 50-90% of 1RM, rest periods of 3-5min between sets allow the opportunity for greater repetitions to be performed . While long rest periods allow mechanical tension to be maximised, as a result, metabolic stress is compromised, which in turn may attenuate the anabolic stimulus to promote muscular hypertrophy [18, 26].
Short rest periods are inclined to produce significant amounts of metabolic stress, thus increasing the anabolic process that is associated with this potential mechanism . However, is it suggested that there is a limiting factor when incorporating short rest periods ’30s, as it does not allow adequate time for an athlete to restore their strength and consequently impairing performance in the following sets [28, 29].
Moderate rest periods appear to be a favourable compromise between short and long rest periods to maximise the balance between muscle strength and hypertrophy. It is demonstrated that moderate rest period of 60-90s between sets is associated with build-up of metabolites, which enhances the secretion of anabolic hormones post-exercise . Additionally, moderate rest periods also help to improve the anabolic environment of the body to a greater level than longer rest periods. For example, moderate rest periods can induce a greater hypoxic environment which enhances the potential for greater muscle growth .
Hormone hypothesis and its adaptations to resistance training
Exercise-induced muscle hypertrophy is mediated by a number of anabolic and catabolic signalling pathways, where activation and interactions of molecular downstream targets shift the balance to favour protein synthesis over degradation to regulate skeletal muscle growth . While there are several complex anabolic signalling pathways that are involved, the mammalian target of rapamycin (Akt-mTor) pathway is understood to act as the primary signalling pathway to regulate skeletal muscle growth . When the Akt-mTor pathway is activated, anabolic signals are then sent to act on downstream targets to enhance muscle protein synthesis leading to skeletal muscle hypertrophy .
While the precise molecular mechanisms involved in the anabolic signalling pathway remain to be elucidated, there is evidence to suggest that the endocrine system may have an influence in the signalling process. Several hormones have been shown to modify the balance between catabolic and anabolic stimuli in the muscle to facilitate a decrease or increase the accretion in muscle proteins . Resistance exercise has been shown to elevate anabolic hormone concentrations in the post-exercise period which increase the likelihood of receptor interactions, thus facilitating a cascade of events to favour protein synthesis and subsequent muscle growth . Several anabolic hormones have been implicated in the proliferation and differentiation of satellite cells, which may facilitate the repair and subsequent growth of new muscle tissue . Various types of resistance training programs have been shown cause acute and chronic alterations in anabolic hormones that may play a role in facilitating hypertrophic adaptations (Figure 2). Out of these hormones that have most widely been studied and will be the focus of this literature review include, insulin-like growth factor-1 (IGF-1), testosterone and GH.
Figure 2. Theoretical sequence of events demonstrating the influence of resistance exercise on hormonal effects leading an increase in hypertrophy and strength. Sourced from Komi 
Insulin-like growth factor-1
Insulin-like growth factor-1 is a peptide hormone that is thought to provide an anabolic response on skeletal muscle . It has been recognised that a cause and effect relationship exists between IGF-1 and muscle hypertrophy , further to this it is alleged that IGF-1 may be the most important regulator of skeletal muscle mass . Moreover, increases in muscle strength following resistance training have been associated with an augmented response of IGF-1 proteins within the muscle , and it has been suggested that mechanical loading appears to magnify the anabolic effects of IGF-1 .
IGF-1 has been shown to act in an autocrine and paracrine manner within the muscle cells . Three isoforms in skeletal muscle have been identified, with each functioning in a different manner, these include; IGF-1Ea and IFG-1Eb, and a splice variant, IGF-1Ec . IGF-1Ea and IGF-1Eb are systemic forms that are predominately produced from the liver. While IGF-1Ec appears to be activated in muscle tissue in response to mechanical loading, as a result, it has been labelled Mechano Growth Factor (MGF)  . While the exact mechanisms of IGF-1’s mode of action have not yet been fully elucidated, it is known that IGF-1 can promote an anabolic effect by increasing the rate of protein synthesis in skeletal muscle [40, 43]. Furthermore, MGF has been shown to activate satellite cell proliferation and differentiation, which is needed for the repair and subsequent growth of new muscle tissue, thus facilitating muscle hypertrophy [44, 45].
Resistance exercise is understood to be the most powerful stimuli for these IGF’s [46, 47]. The performance of hypertrophy type training schemes have been found to produce significantly greater elevations in systemic IGF-1 compared to higher-intensity strength type schemes [18, 26, 48].
These differences in IGF-1 augmentation may partly be explained by the greater accumulation of metabolites and the secretion of systemic anabolic hormones [18, 26, 48]. This is further supported by studies that perform resistance exercise combined with BFR. Where greater increases in IGF-1 levels post-exercise may partly be due to a greater degree of metabolic stress and systemic GH secretion [49-51]. While the aforementioned studies demonstrated acute increases in systemic IGF-1, in contrast several other studies have shown no augmentation in IGF-1 during or immediately post-exercise [52-54]. This may be attributed to the delayed secretion of IGF-1, for example, as peak values may not be reached between 16-28 h after GH-stimulated release  or due to the methodological difference between these protocols. As a result, the acute responses of IGF-1 to resistance exercise remains inconclusive.
Testosterone is a hormone that is synthesised and/or secreted predominantly in the Leydig cells in the testes via the hypothalamic-pituitary-gonadal axis . The acute elevations in testosterone post-exercise are able to directly interact with intracellular androgen receptors, which in turn can lead to a cascade of events to mediate gene transcription . While testosterone may directly influence the anabolic process, it may also have a role in the augmentation of other anabolic hormones such as GH  and IGF-1 , in addition to mediating the proliferation of satellite cells to create a hypertrophic response .
There is a significant amount of evidence supporting the anabolic effects of testosterone on muscle tissue. In support of this, several studies have shown that the administration of exogenous testosterone can promote marked increases in skeletal muscle hypertrophy [58-60], and when combined with resistance exercise this can be further enhanced .
Resistance exercise is understood to have a significant influence on acute elevations of testosterone post-exercise. It has been demonstrated that significant correlations exist between exercise-induced elevations in testosterone and muscle CSA, which suggests that testosterone may play an important role in facilitating muscle hypertrophy .
The magnitude of the testosterone response following resistance exercise is affected by several factors including intensity, volume, exercise selection, and sex , and is independent of the individuals absolute level of muscular strength . There are several different resistance exercise protocols within the literature that have assessed the acute testosterone response. It is suggested that when resistance exercise is performed with moderate loads, high-volume combined with short rest periods (body-building type programs), produce the greatest testosterone response compared to high load, low-volume combined with long rest periods (strength type programs) . Figure 3 displays a summary of the studies that have directly compared the acute testosterone response to hypertrophy vs. strength type resistance exercise schemes. For example, Kraemer et al. , compared the hormonal response to two different resistance training protocols (i) strength scheme, 3-5 sets of 5RM with 3 min rest and (ii) hypertrophy scheme, 3 x 10RM with 1 min rest, both consisting of eight exercises. The results from this study reported that testosterone increases ~20% in the strength scheme compared to ~60% in the hypertrophy scheme, which supports the prevailing body of research between greater increases in testosterone following hypertrophy type resistance training.
Figure 3. Acute testosterone responses from studies that have directly compared hypertrophy and strength resistance type exercise in men.
* denotes significant difference (P <0.05) from corresponding resting or pre-exercise value.
A: Strength; 20 x 1RM rest 3min (Hakkinen and Pakarinen ),B: Strength; 6 x 5 reps at 88% 1RM rest 3min (Smilios et al. ), C: Hypertrophy; 6 x 10 reps at 75% 1RM rest 2min (Smilios et al. ), D: Strength; 15 x 1RM rest 3min constant load (Walker et al. ), E: Strength; 15 x 1RM rest 3min variable load (Walker et al. ), F: Strength; 2 x 5 reps at 88% 1RM rest 3min (Smilios et al. ), G: Hypertrophy; 2 x 10 reps at 75% 1RM rest 2min (Smilios et al. ), H: Power; 8 x 6 jump squats rest 3min (McCaulley et al. ), I: Strength; 4 x 5 reps at 88% 1RM rest 3min (Smilios et al. ), J: Hypertrophy; 4 x 10 reps at 75% 1RM rest 2min (Smilios et al. ), K: Endurance; 2 x 15 reps at 60% 1RM rest 1min (Smilios et al. ), L: Hypertrophy; 3 x 10RM rest 3min (Kraemer et al. ), M: Strength; 11 x 3 reps at 90% 1RM rest 5min (McCaulley et al. ), N: Hypertrophy; 5 x 10 reps ay 80% 1RM rest 3min constant load (Walker et al. , O: Strength; 4 x 4 reps at 90%
1RM rest 3min (Hoffman et al. ), P: Hypertrophy; 4 x 15 reps at 60% 1RM rest 3min (Hoffman et al. ), Q: Endurance; 4 x 15 reps at 60% 1RM rest 1min (Smilios et al.  , R: Hypertrophy; 5 x 10RM rest 3min (Kraemer et al. ), S: Hypertrophy; 5 x 10 reps ay 80% 1RM rest 3min variable load (Walker et al. , T: Strength; 5 x 5RM rest 3min (Kraemer et al. ), U: Hypertophy; 3 x 5RM rest 1min (Kraemer et al. , V: Hypertrophy; 3 x 10RM rest 1min (Kraemer et al. ), W: Hypertrophy; 4 x 10 reps at 75% 1RM rest 90s (McCaulley et al. ), X: Hypertrophy; 10 x 10 reps at 70% 1RM rest 3min (Hakkinen and Pakarinen ), Y: Hypertrophy; 5 x 5RM rest 1min (Kraemer et al. .
Growth hormone is a polypeptide hormone that is secreted and released by the anterior pituitary gland in a pulsatile fashion, with the greatest secretions occurring during the early phases of sleep . Growth hormone represents a ‘superfamily’ of polypeptide growth factors that is known for their anabolic effects on muscle tissue , with the main circulating 22Kda molecule (which consists of 191 amino acids) being the most studied GH variant within the literature [20, 35].
Growth hormone has been considered to have both anabolic and catabolic properties . Additionally, GH is known to stimulate cellular uptake, induce fat metabolism by the mobilisation of triglycerides, and integrate specific amino acids into various proteins, including those in skeletal muscle . The anabolic effects of GH on skeletal muscle are thought to have both direct and indirect actions, and some of the effects are thought to be mediated through the actions of IGF-1 in an autocrine and paracrine fashion to promote hypertrophic adaptations . There is a significant amount of research supporting this belief, as it has been shown that circulating IGF-1 levels are increased following the administration of GH [40, 71, 72]. Furthermore, there is wealth of research suggesting that the administration of exogenous GH in GH deficient populations have been shown to reduce body fat and more importantly increase muscle mass . As a result of this observation, it has led to the belief that GH may play a significant anabolic role in skeletal muscle growth.
Acute elevations in GH concentrations post-exercise are extremely sensitive to resistance training. Specifically, it has been demonstrated that an exercise-induced increase in GH levels have been highly correlated with the magnitude of skeletal muscle hypertrophy (both in type I and type II muscle fibers) . The magnitude of the GH response to resistance training appears dependant on the intensity, volume, rest periods, exercise selection and sex . Similar to testosterone, hypertrophy type schemes (moderate-intensity, high-volume, short rest) have shown to produce the greatest GH response compared to conventional strength type schemes (high-intensity, low-volume, long rest) . A summary of the studies that have directly compared the acute GH response to hypertrophy vs. strength type resistance exercise protocols are displayed in Figure 4.
For example, Hakkinen and Pakarinen  compared the acute hormonal response to two different heavy resistance protocols in male athletes (1) 10 sets x 10 reps at 70% 1RM of the squat exercise (hypertrophy scheme) and (ii) 20 x 1RM at 100% 1RM (strength scheme). It was reported that the strength scheme produced a slight increase in GH (not significant), while a substantial increase in GH was observed in the hypertrophy scheme. It is suggested that the acute GH response to resistance exercise is highly influenced by the total work completed and its metabolic properties . Thus, resistance exercise protocols that elicit higher blood lactate levels tend to produce the greatest augmented response in GH (protocols that typically incorporate hypertrophy schemes) [17, 18, 26, 64]. Furthermore, high correlations have been reported between blood lactate and GH concentrations , and it has been proposed that the accumulation of hydrogen ions produced by the build-up of lactate may be the most important factor influencing the release of GH .
Figure 4. Acute growth hormone responses from studies that have directly compared hypertrophy and strength resistance type exercise in men.
* denotes significant difference (P <0.05) from corresponding resting or pre-exercise value.
A: Strength; 20 x 1RM rest 3min (Hakkinen and Pakarinen ,B: Strength; 5 x 5 reps at 90% 1RM rest 3min (Goto et al. ), C: Strength; 5 x 5 reps at 90% 1RM rest (extra set at 90% 1RM; 4 reps) (Goto et al. ), D: Strength; 15 x 1RM rest 3min constant load (Walker et al. , E: Hypertrophy; 3 x 10RM rest 3min (Kraemer et al. , F: Hypertrophy; 5 x 10RM rest 3min (Kraemer et al. ), G: Hypertrophy; 3 x 5RM rest 1min (Kraemer et al. ), H: Strength; 4 x 5 reps at 88% 1RM rest 3min (Zafeiridis et al. ), I: Strength; 2 x 5 reps at 88% 1RM rest 3min (Smilios et al. ), J: Strength; 4 x 4 reps at 90% 1RM rest 3min (Hoffman et al. ), K: Strength; 4 x 5 reps at 88% 1RM rest 3min (Smilios et al. , L: Strength; 6 x 5 reps at 88% 1RM rest 3min (Smilios et al. ), M: Strength; 5 x 5RM
rest 3min (Kraemer et al. ), N: Strength; 5 x 5 reps at 90% 1RM rest (extra set at 70% 1RM; 13 reps) (Goto et al. ), O: Strength; 15 x 1RM rest 3min variable load (Walker et al. , P: Hypertrophy; 2 x 10 reps at 75% 1RM rest 2min (Smilios et al. , Q: Strength; 5 x 5 reps at 90% 1RM rest (extra set at 50% 1RM; 25 reps) (Goto et al. ), R: Hypertophy; 3 x 5RM rest 1min (Kraemer et al. ), S: Hypertrophy; 6 x 10 reps at 75% 1RM rest 2min (Smilios et al. ), T: Hypertrophy; 4 x 15 reps at 60% 1RM rest 3min (Hoffman et al. ), U: Hypertrophy; 4 x 10 reps at 75% 1RM rest 2min (Zafeiridis et al. ), V: Hypertrophy; 4 x 10 reps at 75% 1RM rest 2min (Smilios et al. ), W: Endurance; 2 x 15 reps at 60% 1RM rest 1min (Smilios et al. ), X: Hypertrophy; 5 x 10 reps ay 80% 1RM rest 3min constant load (Walker et al. ), Y: Hypertrophy; 5 x 10 reps ay 80% 1RM rest 3min variable load (Walker et al. ), Z: Endurance; 4 x 15 reps at 60% 1RM rest 1min (Smilios et al. ), AA: Endurance; 4 x 15 reps at 60% 1RM rest 1min (Zafeiridis et al. ), BB: Hypertrophy; 3 x 10RM rest 1min (Kraemer et al. ), CC: Hypertrophy; 10 x 10 reps at 70% 1RM rest 3min (Hakkinen and Pakarinen ).
Hypoxia and resistance exercise: Applications to muscle strength and hypertrophy
Resistance exercise combined with blood flow restriction
Over the last decade, blood flow restriction, also known as occlusion training, has received a significant amount of attention. This technique involves the application of an inflatable pressure cuff around the proximal end of the limb to occlude distal blood flow, therefore creating a local hypoxic environment during exercise . As a result, BFR training is usually performed at low-intensity (‘50% 1RM), with a set range of 3-5 at ~ 15 repetitions (or to volitional fatigue), combined with short rest periods of ‘ 60 s . Blood flow restriction training has been suggested to be an effective training modality for athletes , injury rehabilitation patients, and the elderly [51, 80], and is currently endorsed as a novel training method that is able to enhance muscular strength and hypertrophy . The Amercian College of Sports Medicine typically recommends resistance training to be performed at an intensity ‘65% of 1RM to achieve optimal gains in muscle hypertrophy . It is believed that resistance exercise performed below this threshold intensity rarely produces significant gains in muscle strength and hypertrophy . However, several studies that have incorporated BFR training schemes have demonstrated significant increases in muscle strength and hypertrophy following 2-16 wk of training at intensities as low as 20% 1RM [49, 79, 83, 84]. Although, the precise mechanisms of BFR training on muscular hypertrophy are yet to be fully elucidated, it is proposed that a combination of factors including, a greater accumulation of metabolites and subsequent increase in anabolic hormone concentrations, enhanced motor unit recruitment and intramuscular cell signalling .
Proposed mechanisms for blood flow restriction training
Recruitment of muscle fibers
Under normal conditions the size principle suggests that type I fibers (slow twitch) are recruited first and as the intensity increases, type II fibers (fast twitch) are then recruited . It is postulated that during occlusion there is a reduction of oxygen available to the muscle (thus creating a hypoxic environment), where lower threshold type I motor units are expected to fatigue more rapidly, that a progression of additional motor units are recruited (type II) to maintain the same level of force production . This supposition has been supported by several studies that have assessed motor unit activity with the use of electromyography (EMG), demonstrating that there is no practical difference in EMG between low-intensity BFR training and high-intensity training (without the use of BFR), suggesting that a sufficient number of fast twitch fibers are activated even at these low intensities [11, 88, 89]. The proposed mechanism for the recruitment of higher threshold motor unit following BFR training is associated with metabolic accumulation cause by reduce oxygen availability, stimulate group III and IV afferents, which may inhibit alpha motor neurons, leading to an increased fiber recruitment to maintain force and protect against conduction failure . As a result, BFR training may have the potential to maximise muscle strength and hypertrophic adaptations even at training with low intensities.
There is evidence to suggest that metabolic stress may contribute to skeletal muscle hypertrophic adaptations . Resistance exercise combined with BFR has demonstrated significant elevations in the accumulation of metabolites in particular, increased inorganic phosphate (Pi) [92, 93], phosphocreatine depletion [92, 94], decreased pH [92, 94] and increases in lactate production [11, 50, 51, 95, 96]. One of the most prominent studies by Takarada et al.  investigated the effects of 5 sets of ~14 repetitions of bilateral knee extension exercise at 20% 1RM, combined with or without BFR on several physiological responses. It was reported that the increase in blood lactate double in the BFR group compared to control immediately post exercise. Furthermore, it has also been suggested that following BFR training a strong correlation exits between metabolic stress (measured by a decrease in pH and increase in Pi) and muscle CSA . Therefore, it is proposed that the reduction in oxygen availability to the working muscle following BFR training restricts the ability for the clearance of lactate, thus increasing the reliance on anaerobic metabolism . This augmented metabolic response is theorised to promote hypertrophic adaptations through the elevation in anabolic hormones, increased type II fiber recruitment, intramuscular cell signalling and cell swelling .
Numerous studies have investigated the effects of resistance exercise combined with BFR and demonstrated alterations on hormonal responses. Further to this, several studies have reported significantly greater increases in GH concentrations when resistance exercise was combined with BFR compared to without [11, 51, 84, 95, 96, 98]. One study reported a rapid increase in GH concentrations of ~290 times greater than baseline measurements in the BFR group, with no significant changed observed in the control group . Furthermore, a four-fold increase in GH concentrations was observed following resistance exercise combined with BFR (3 sets of repetitions completed to volitional fatigue at 30% 1RM), whereas no significant change in GH was observed following the same procedures at 70% 1RM without BFR . It is postulated that acute elevations in GH concentrations are mediated by the build-up in H+ and/or lactate in the blood [64, 99], causing a reduction in pH, which may potentiate the secretion of GH, through a chemoreceptive reflex mediated by intramuscular metaboreceptors and group III and IV afferent fibers [85, 100].
Only a few selected studies have reported concomitant increases GH levels and upregulation of IGF-1 following low-intensity BFR training [49, 51], which is similar to the responses observed following resistance training at high-intensity without BFR [101, 102]. However, several other studies that have performed low-intensity (20% 1RM) resistance exercise combined with BFR have reported no change in IGF-1 levels, even though an increase in GH was observed [50, 98]. The difference in these results may be attributed to the delayed IGF-1 response, as peak values may not be reached between 16-28 h after GH release .
Furthermore, low-intensity resistance exercise combined with BFR does not appear to augment the testosterone response [50, 96]. This may be explained by the protocols either being too low in volume or intensity, as a threshold for these variables must be met to elicit a significant testosterone response .
Resistance exercise is associated with a mechanical disruption that is able to activate the mTOR signalling pathway, which plays a significant role in stimulating muscle protein synthesis via translation and initiation . Ribosomal S6 kinase 1 (S6K1) is a key downstream regulator of the mTOR pathway that is involved in the regulation of mRNA translation initiation and, as a result, is critical to enhance muscle protein synthesis and subsequently skeletal muscle hypertrophy .
A prominent study by Fujita et al.  demonstrated an increase S6K1 phosphorylation following low-intensity BFR exercise at 20% 1RM, in addition to, a significantly greater increase in muscle protein synthesis at 3 h post-exercise, while no change was observed in the control group. Similarly, Fry et al.  reported a significant increase in both S6K1 phosphorylation and muscle protein synthesis in the BFR group 3 h post-exercise following four sets and 75 repetitions at 20% 1RM bilateral knee extensions, while no change was observed in the control group performing the identical protocol. More recently, Werbom et al.  reported a significant increase in mTOR signalling 1 hr post exercise following unilateral knee extension at 30% of 1RM to failure in the BFR trained leg compared to the control leg. While an enhanced mTOR signalling was observed following BFR training, it was also noted that there was no difference in mTOR signalling at 24 h post-exercise between both conditions. Therefore, it may be difficult to assess the influence of mTOR signalling in concert with systemic responses and local growth factors .
Resistance exercise and systemic hypoxia
Hypoxic exercise is alternative training method where the amount of oxygen available to the muscle is reduced by breathing hypoxic air, has been reported to improve both aerobic  and anaerobic  performance in athletes. Additionally, it has also been shown that power output can be improved following high-intensity cycling in hypoxia , while others have found substantial improvements in muscular strength [111, 112]. Given that the aim of BFR is to reduce the oxygen delivery and availability to the muscle to create a localised hypoxic environment, it is possible that similar responses may be observed when performing resistance exercise in systemic hypoxia .
Physiological responses to resistance training in hypoxia
Muscle cross sectional area
While RTH is in its infancy, there a few studies that have reported augmented changes in muscle CSA [111-114]. A novel study that compared the effects of 5 wk of low-intensity (20% 1RM) resistance exercise in hypoxia and normoxia, reported greater increases in muscle CSA of the knee extensors and flexors in hypoxia compared to the identical training in normoxia (6.1 ?? 5.1 vs. 2.9 ?? 2.75) . Similarly, Nishimura et al.  reported a significant increase in elbow flexor and extensor muscle CSA following 6 wk of moderate-intensity (70% 1RM) in hypoxia (16% inspired O2), whilst no significant change was observed after identical training normoxia. In contrast, Friedmann et al.  reported that 4 wk of low-intensity (20% 1RM)/high repetition knee extension exercise in hypoxia (12% inspired O2) did not induced any significant changes in muscle CSA. Nonetheless, no significant changes were also observed in the normoxic group, therefore, it was suggested that RTH was not a superior training modality to the identical training normoxia.
While there are disparities in these investigations, it is important to consider the influence of the methodological designs on the changes in muscle CSA. Particularly, the program durations as Friedman et al.  employed a training study of 4 wk, which may not be sufficient to stimulate muscular hypertrophy. Collectively, this data suggest that RTH may be beneficial to promote skeletal muscle hypertrophy, which is similar to that observed following BFR training, and beyond those achieved by training in normoxia.
Hormonal and metabolic responses
To date, there are only two studies that assessed the acute hormonal and metabolic response to RTH [116, 117]. Kon et al.  investigated the effects of bench press and leg press exercise at 70% 1RM consisting of 5 sets of 10 repetitions combined with one minute rest intervals in systemic hypoxia (13% inspired O2) and normoxia (21% inspired O2). It was reported that the hypoxic group demonstrated significantly greater increases in both blood lactate (1.3-fold) and GH (mean value 12.9 ?? 2.5 vs. 7.7 ?? 1.9 ng/mL) responses compared to the normoxic group. Similar findings were reported from the same research group when resistance exercise was performed at 50% 1RM consisting of 5 sets of 14 repetitions at 13% inspired O2 . However, it was also reported that there was no significant difference in both serum testosterone and IGF-1 following low-intensity resistance exercise in both hypoxia and normoxia [116, 117]. These findings are in agreement with the responses observed following BFR training, where the GH response is typically augmented, whilst testosterone and IGF-1 do not appear to be significantly altered.
More recently, two studies have investigated the effects of moderate-intensity resistance exercise (70% 1RM) in systemic hypoxia over eight week duration [113, 114]. Both studies assessed the GH response on the first and last resistance exercise session and it was reported that the hypoxic group observed a significantly greater increase GH concentrations compared to the normoxic group. Further to this, peak GH levels were similar in both the first and last session following RTH, while no such GH response was observed in the normoxic group. These findings suggest that the hypoxic stimulus may be able to still have an influence on the anabolic hormonal response following repeated bouts of the same training regimen, thus potentially augmenting a hypertrophic response.
To this point, only one study has investigated the effects of resistance exercise in hypoxia on muscle protein synthesis and anabolic signalling. Etheridge et al.  reported that following moderate-intensity (70% 1RM) resistance exercise (6 sets of 8 repetitions) under hypoxic conditions (12% inspired O2 for 3.5 h), demonstrated a blunted response in muscle protein synthesis despite observing an increase in S6K1 phosphorylation. This finding is somewhat in contrast to what is reported following BFR training, where it has been reported that increases in S6K1 phosphorylation are associated with increases in muscle protein synthesis [50, 105]. While the results may indicate that resistance exercise in acute systemic hypoxia may blunt muscle protein synthesis, it should be noted that participants were exposed to hypoxia for 3.5 h, where chronic exposure has been suggested to promote atrophying effects on skeletal muscle , thus diminishing any anabolic effects. Therefore, the intramuscular cell signalling response to RTH remains to be elucidated. A simplified schematic of the proposed mechanisms that may affect hypertrophic adaptions to BFR and RTH training modalities is displayed in Figure 5.
Figure 5. A schematic of the proposed mechanisms by which blood flow restriction (BFR) and resistance training in systemic hypoxia (RTH) may facilitate muscle hypertrophy and strength.
Differences between blood flow restriction and systemic hypoxic resistance training methods
Low-intensity resistance exercise combined with BFR has the potential to reduce the stress on the ligaments and joints of the body when compared to resistance exercise at higher intensity (i.e. >70 % 1RM) , thus decreasing the incidence the injury whilst still promoting muscular strength and hypertrophy adaptations [79, 89]. As a result, BFR training can stimulate muscular adaptations in diverse populations that display compromised joint stability and/or strength such as injury rehabilitation patients or the elderly . Furthermore, due to the low mechanical stress and subsequent reduced muscle damage and inflammation placed on the musculoskeletal system , low-intensity BFR training does not require a large amount of recovery time between training sessions . Consequently, it is possible to perform BFR training at higher training frequencies compared to traditional resistance training programmes . While BFR training appears to facilitate gains in muscle hypertrophy and strength, it is important to note there are some limitations with this training modality. As low-intensity BFR training may result in enhanced muscle CSA and strength, a concomitant increase in the connective tissue strength may not transpire compared to training at higher-intensities (i.e. 80% 1RM) due to the reduction in mechanical load .
Further to this, there are some practical limitations when performing BFR training such as the equipment and the expertise required to perform such training, in addition to the logistics of using blood pressure cuffs with large groups. Although, it has been suggested that a more feasible option is the use of elastic wraps to occlude blood flow , it is difficult to monitor the occlusive pressure with this technique. More importantly, without the appropriate experience in applying cuffs or elastics wraps there are some potential physiological risks such as dizziness, numbness, chills, and petechial haemorrhage under the skin . Furthermore, BFR is only limited to training specific limbs and consequently training of the whole body musculature is eliminated.
To overcome these limitations, the use of systemic hypoxia instead of BFR is an alternative training modality that appeals to individuals to promote strength and hypertrophic adaptations. Although similar morphological and physiological responses have been observed following RTH, the exposure to severe hypoxia has been proposed to alter function of the central nervous system, and it is conceivable that systemic hypoxia may affect motor unit recruitment , however, this remains to be elucidated in RTH research.
While both BFR and RTH modalities are predominately mediated by the hypoxic stimulus whether it is local or systemic, RTH may be more beneficial for athletic populations, as it allows individuals to train at higher intensities and the ability to perform multi-joint exercise under hypoxic conditions.
Strength or resistance training being shown to significantly improve various athletic qualities (i.e. strength, power and speed) . Therefore, it is necessary for athletes to consistently perform strength training programs in order to improve their performance. There are various forms of resistance training programmes that athletes currently undertake with the aim to enhancement performance through increases in muscle strength and hypertrophy .
Hypertrophy and strength gains following resistance training are believed to be dependent on the manipulation of acute training variables, in particular the intensity of exercise . Traditionally, it is recommended that resistance exercise be performed at an intensity of more than 65% of 1RM to achieve a substantial effect for hypertrophy and strength adaptations . It has been shown that resistance training increases hypertrophy and strength gains via a combination of mechanical, metabolic, neural and hormonal factors .
Anabolic hormones such as GH and testosterone are thought to play an integral role in promoting muscle hypertrophy [56, 68]. Resistance exercise has been shown to produce acute increases in these anabolic hormones . The augmentation of these systemic hormones have been shown to be highly correlated to significant increases in muscle hypertrophy, with body-building (moderate-intensity, high-volume) type schemes producing greater elevations in anabolic hormones compared to traditional strength training protocols (low-volume, high-intensity) .
A novel training method that combines low-intensity resistance training with BFR has been shown facilitate muscular strength and hypertrophic adaptions through multiple factors including, metabolic stress, enhanced motor unit recruitment, intramuscular cell signalling, and elevated hormonal production . This training modality is predominately mediated by the hypoxia stimulus and is typically performed at low-intensity (‘50% 1RM) , which is well below the recommended threshold for strength and hypertrophic adaptations. Recently, it is suggested that RTH can elicit similar physiological responses to that observed following BFR training, and it considered that there is a potential benefit of performing RTH to promote increases in muscle strength and hypertrophy [111, 117]. Therefore, a great benefit will be gained by understanding whether RTH is advantageous to further maximise strength and hypertrophic adaptations, and the aim of this investigation was to advance the knowledge about this relationship.
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