The main findings of the present investigation were: 1) the combination of CR supplementation and structured resistance training increased muscular strength, isokinetic peak torque, and muscle CSA, irrespective of the rest interval length between sets, 2) progressively decreasing the rest interval length between sets, although not negatively impacting muscular strength and CSA adaptations to resistance training, significantly impaired exercise acute repetition performance within a given workout (more for upper body exercise than for lower body exercise), and 3) it did not appear as though CR supplementation attenuated the decrease in acute repetition performance with progressively shorter rest intervals between sets. However, based on this final statement, our failure to include a true control group not receiving CR supplementation but undergoing a progressive decrease in rest interval length does not allow us to make such a statement with absolute confidence, regarding the ability of CR to off-set any additional decrease in training volume that may have been apparent. This is indeed a limitation of the present work and should be a focus of future research.
A previous study from our research group  compared the effect of 8-weeks of resistance training using CI and DI between sets and exercises on strength and hypertrophy. Recreationally resistance training subjects were randomly assigned to either a CI or DI training group. The results indicated no significant differences between the CI and DI training protocols for CSA, 1RM and isokinetic peak torque. Similar to the current study, these results  indicated that a training protocol with DI was as effective as a CI protocol over short training periods (8-weeks) for increasing maximal strength and muscle CSA.
Muscle mass is important for health and survival through the lifespan . Resistance training has been recognized as an essential component of a comprehensive fitness program for individuals with diverse fitness goals . Manipulation of training variables (e.g. load, volume, rest interval between sets) is dependent on the specific training goals of the individual and the nature of the physical activities performed during daily life [20, 21]. The length of rest interval must be sufficient to recover energy sources (e.g., adenosine triphosphate [ATP] and PCR), buffer and clear fatigue producing substances (e.g., H+ ions), and restore force production .
Certain ergogenic substances have been shown to augment resistance training adaptations beyond that which may occur through resistance training alone. With regard to the function of the Phosphagen energy system, the ergogenic value of CR supplementation has been examined extensively with significant benefits reported in strength/power, sprint performance, and/or work performed during multiple sets of maximal effort muscle contractions [1, 2, 23–25]. The improvement in exercise capacity has been attributed to increased total creatine (TCR) and PCR content, thus resulting in greater resynthesis of PCR, improved metabolic efficiency and/or an enhanced quality of training; thus promoting greater neuromuscular adaptations.
The increased muscle strength and improved weightlifting performance following CR ingestion plus resistance training could result from several mechanisms, including greater gains in lean body mass  and an increase in the intensity of individual workouts, resulting from a better ability to meet energy demands during exercise . We contend that the beneficial effects of CR supplementation on muscle strength and weightlifting performance during resistance training are largely the result of the CR-loaded subjects ability to train at a higher workload than placebo-supplemented subjects, as suggested previously [27, 28]. However, while this may be the case when maintaining rest interval length, our present data indicate that when rest interval length is decreased significantly, the total training load is decreased despite CR supplementation.
Although we did not include a true control group that did not receive CR supplementation but underwent training using a progressively decreasing rest interval; it is plausible that CR may attenuate the decrease in training volume when subjects are exposed to such a condition. Regardless, and perhaps of most importance to athletes who use CR for purposes of increasing strength and muscle mass, the volume of training was greater for the CI group versus the DI group but strength gains were similar between groups. Thus, the creatine supplementation appeared to bolster strength gains particularly for the DI group, even in the presence of significantly less volume. However, future work is needed to investigate the relationship between CR supplementation versus no supplementation on volume parameters and strength and muscle mass increases during long term studies.
In long-term studies, subjects taking CR typically gain about twice as much body mass and/or fat free mass (i.e., an extra 2 to 4 pounds of muscle mass during 4 to 12 weeks of training) versus subjects taking a placebo [29, 30]. The gains in muscle mass appear to be a result of an improved ability to perform high-intensity exercise via increased PCR availability and enhanced ATP synthesis, thereby enabling an athlete to train harder to promote greater muscular hypertrophy via increased myosin heavy chain expression; possibly due to an increase in myogenic regulatory factors myogenin and MRF-4 [31–33]. In the present study, we clearly noted a reduction in training volume for the DI group.
We speculate that because the loads for the current study were in the 8-10 RM range, perhaps anaerobic glycolysis was being emphasized to a greater extent for ATP production. As the rest intervals were progressively shorter in the DI group, there would have been limited time to resynthesize PCr, and greater reliance would have been placed on rapid glycolysis to effectively meet energy demands. Therefore, creatine supplementation might be more effective in maintaining volume with higher loads and less repetitions per set (e.g. one to six repetition maximum per set). Despite this, subjects in the DI group maintained similar adaptations in muscle strength and CSA as compared to subjects in the CI group. It is possible that subjects' overall perceived effort and intensity plays a significant role in the adaptive process, as opposed to simply the absolute volume load. That is, all subjects adapted to a similar degree, yet those in the DI group demonstrated significant reductions in volume load versus the CI group (see Tables 1 and 2).
According to the Position Statement of International Society of Sports Nutrition, CR monohydrate (and not other forms of CR) is the most effective ergogenic nutritional supplement currently available to athletes in terms of increasing high-intensity exercise capacity and lean body mass during training . To date, several hundred peer-reviewed research studies have been conducted to evaluate the efficacy of CR supplementation in improving exercise performance. Nearly 70% of these studies have reported a significant improvement in exercise capacity, while the others have generally reported non-significant gains in performance .
Arciero et al.  compared 1-RM strength gains after 4 weeks of CR supplementation with or without resistance training. Bench press and leg press 1-RM were increased 8 and 16%, respectively, in the CR alone group and 18 and 42%, respectively, in the training group. This study suggests that approximately 40% of the increase in strength over the 4-week training and CR supplementation period is due to the acute effects of CR on force production, with the remaining 60% due to some other mechanism, presumably an ability to train with higher workloads. Syrotuik et al.  reported that when training volume is equal, subjects ingesting CR or placebo experienced similar increases in muscle strength and weightlifting performance following an 8-week resistance training program. Thus, it is probable that subjects who ingest CR during resistance training do more work than those who do not [32, 33]. Again, this assumes that rest interval length remains constant, unlike the present design.
Larson-Meyer et al.  conducted a double-blind, placebo-controlled study, which involved 14 division I female soccer players during their 13-week off-season resistance training program. Seven of the women were CR loaded with approximately 7.5 g twice daily for 5 days, and then maintained their CR intake at 5 g/day for the remainder of the study. Following a repeated measures analyses to establish trial by group interactions, it was determined that bench-press and squat 1-RM strength improved more for the CR group compared with the placebo group. There was, however, no difference between the two groups concerning overall gains in lean tissue as determined by dual energy x-ray absorptiometry (DXA).
To our knowledge, the current study was the first to compare the chronic effects of CR supplementation in a training program using decreasing rest intervals between sets and exercises to a program using constant rest intervals. In strength-type regimens, the recommended rest interval of 2-5 minutes between sets has been shown to allow for consistent repetitions, without large reductions in the load [37–40]. Conversely, in hypertrophy-type regimens, the recommended rest interval of 30-90 seconds is not sufficient to sustain the load and/or repetitions over consecutive sets [41, 42]. Our data clearly indicate that, despite CR supplementation, reduction of rest interval length below 105 seconds (week 4; 90 seconds) significantly impairs exercise performance (in particular as related to bench press performance).
The need for longer rest intervals when emphasizing strength are supported by Pincivero et al.  for isokinetic training with either 40 seconds or 160 seconds rest between sets. One leg of each subject was assigned to a four week, three days per week isokinetic protocol that involved concentric knee extension and flexion muscle actions performed at 90°·s-1. The 160 second rest group demonstrated significantly greater increases in quadriceps and hamstring peak torque (60°·s-1), average power (60°·s-1), and total work (30 repetitions at 180°·s-1).
In the current study, despite a decrease in training volume load in the DI group, both groups showed significant increases pre- to post-training in knee extensor and flexor isokinetic peak torque. No significant difference between the DI and CI groups in peak torque at an angular velocity of 60°·s-1 was shown indicating isokinetic peak torque is equally increased with both CI or DI training groups.
Robinson et al.  demonstrated findings that were consistent with Pincivero et al.  for free weight training. In this study, the effects of three different intervals (3 minutes, 90 seconds and 30 seconds) were compared on maximal back squat strength. Thirty-three moderately trained college age men performed a free weight training program four days per week for five weeks. The group that rested 3 minutes between sets demonstrated significantly greater increases in maximal back squat strength versus the 90 second and 30 second rest groups.
Conversely, Willardson and Burkett  compared back squat strength gains and volume components in 15 recreationally trained men that were divided into a 2 minute rest group and a 4 minute rest group. Each group performed the same training program, with the only difference being the length of the rest interval between sets. Subjects performed two squat workouts per week. The squat workouts varied in the load, number of sets, and repetitions performed per set in a nonlinear periodized manner. Differences in strength gains and volume components (the load utilized per set, the repetitions performed per set, the intensity per set, and the volume performed per workout) were compared between groups. The key finding was that during the entire training period; the 4 minute group demonstrated significantly greater total volumes during the higher intensity workouts. However, the groups were not significantly different in back squat strength gains. These findings suggest that there was a threshold in terms of the volume necessary to gain a certain amount of strength, similar to the current study in which the DI group made similar strength gains as the CI group.
Creatine supplementation has multiple metabolic effects and may possibly influence the hormonal response to exercise and subsequent hypertrophy . If so, this may help to explain our findings of improved muscle strength and CSA despite a reduction in training volume load for the DI group. Ahtiainen et al.  indicated that hormonal responses and hypertrophic adaptations did not vary with 2 or 5 minute rest intervals in 13 recreationally trained men (with an experience of 6.6 ± 2.8 years of continuous strength training). This experiment involved a cross-over design so that two groups trained 3 months with each rest condition. The maximal strength of the leg extensors and quadriceps CSA was assessed before and after completion of each condition. Other variables that were assessed included: electromyographic activity of leg extensor muscles, concentrations of total testosterone, free testosterone, cortisol, growth hormone, and blood lactate. The results demonstrated that for both conditions, acute responses and chronic adaptations were similar in terms of the hormonal concentrations, strength development, and increases in quadriceps CSA. A key finding by Ahtiainen et al.  was that the 5 minute rest interval allowed for the maintenance of a higher training intensity (approximately 15% higher); however, the volume of training was equalized so that the 2 minute condition required more sets at a lower intensity, while the 5 minute condition required less sets at a higher intensity. Thus, the strength and hormonal responses appeared to be somewhat independent of training intensity as long as an equal volume was performed.
Buresh et al.  also compared the chronic effects of different inter-set rest intervals after 10 weeks of strength training. Twelve untrained males were assigned in strength training programs using either 1- or 2.5-minute rest between sets, with a load that elicited failure only on the third set of each exercise. Measures of body composition, hormone response, thigh and arm indirectly CSA, and 5 RM loads on squat and bench press were assessed before and after 10 weeks program. The results showed that 10 weeks of both strength training programs resulted in similar significant increases in 5 RM squat and bench press strength, thigh and arm CSA, and lean mass. However, 1-minute of rest between sets elicited a greater hormonal response versus 2.5-minutes of rest between sets during the first training weeks, but these differences disappeared after 10 weeks of training. These results suggested that acute hormonal responses may not necessarily be predictive of hypertrophic gains after 10 weeks training program performed by untrained healthy males . Considering all available evidence, it appears that multiple factors are involved in strength and hypertrophy development, including but likely not limited to perceived subject effort, training volume, training intensity, metabolic factors associated with recovery, and acute and long-term hormonal responses.