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Accepted Manuscript

Muscle growth across a variety of exercise modalities and intensities: Contri-

butions of mechanical and metabolic stimuli

Hayao Ozaki, Jeremy P. Loenneke, Samuel L. Buckner, Takashi Abe

PII: S0306-9877(16)00009-8
Reference: YMEHY 8150

To appear in: Medical Hypotheses

Received Date: 8 October 2015

Accepted Date: 29 December 2015

Please cite this article as: H. Ozaki, J.P. Loenneke, S.L. Buckner, T. Abe, Muscle growth across a variety of exercise
modalities and intensities: Contributions of mechanical and metabolic stimuli, Medical Hypotheses (2016), doi:

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Muscle growth across a variety of exercise modalities and intensities: Contributions of

mechanical and metabolic stimuli

Hayao Ozaki, Ph.D1, Jeremy P. Loenneke, Ph.D2, Samuel L. Buckner, Ph.D2, Takashi Abe, Ph.D3

School of Health and Sport Sciences, Juntendo University, Inzai, Chiba 270-1695, Japan

Department of Health, Exercise Science, & Recreation Management, KevserErmin Applied

Physiology Laboratory, School of Applied Sciences, The University of Mississippi, University, MS

38677, USA

National institute of Fitness and Sports in Kanoya, Kanoya, Kagoshima 891-2393, Japan

Address for Correspondence to:

Hayao Ozaki, School of Health and Sports Science, Juntendo University, 1-1 Hirakagakuendai,

Inzai, Chiba, Japan

TEL: (+81) 47698-1001, FAX: (+81) 47698-1030


This paperreviewsthe existing evidence for the potential contribution of metabolic

and mechanical stimuli to muscle growth in response to a variety of exercise modalities and

intensities. Recent research has demonstrated that low-load resistance training can elicit

comparable hypertrophy to that of high-load resistance trainingwhen each set is performed

until failure. The degree of metabolic fatigue would be greater for resistance training with

lower loads compared to higher loads at the point of muscle failure, which may compensate for

the lower mechanical stress.This may also explain why muscle hypertrophy occurs to varying

magnitudes when activities such as cycling and walking are performed. Furthermore, the

application of blood flow restriction to the working muscles during these activities induces

greater hypertrophy albeit at the same level of mechanical stress, which would suggest a

possible contribution from metabolic stress. Thus, it is plausible that both mechanical and

metabolic stimuliare primary mechanisms for muscle hypertrophy and the degree of

contributions of both stimuli determines the exercise-induced muscle hypertrophy.


Skeletal muscle is important for carrying out activities of daily living and plays an

important role with metabolism. For example, skeletal muscle functions as the largest disposal

site for ingested glucose[1], plays a role in lipid oxidation and in immune responses[2,3], and

contributes to the resting metabolic rate[4]. Thus, strategies to increase or maintain this tissue

across the lifespan are important for overall health.Exercise training with a high external load

or high mechanical tension has been primarily recommended for maximizing muscle

hypertrophy[5]. Interestingly, recent research has demonstrated that, when each set is

performed until failure, low-load resistance training can elicit comparable hypertrophy to that

of high-load resistance training[6,7]. At the point of failure, the magnitude of metabolic fatigue

would be greater for resistance training with lower loads compared to higher loads, given that

one cannot continue lifting even with lighter weights. This greater metabolic fatigue may

compensate for the lower mechanical stress[8]and may also explain why activities such as

cycling and walking have also been shown to stimulate muscle growth to varying

magnitudes[9,10]. In addition, blood flow restriction (BFR) applied to the working muscles

during these activities induces greater hypertrophic effects albeit at the same level of

mechanical stress[11,12], which would suggest a possible contribution from metabolic stress.

Thus, both mechanical tension and metabolic stress appear to be primary mechanisms for
muscle hypertrophy[8]. Taken together, it is plausible that the degree of contributions of both

mechanical tension and metabolic fatigue determines the exercise-induced hypertrophic

effect[8]. Thus, the purpose of this manuscript is to review the evidence for muscle growth

across a variety of exercise modalities/intensities and discuss the potential interaction between

metabolic and mechanical stimuli.

Procedure for making Figure

Figure 1 displays the relationship between the training-induced muscular hypertrophic

response to resistance exercise until failure or typical aerobic exercise (Figure 1A), as well as

during resistance or aerobic exercise with BFR (Figure 1B). The exercise stimulus involves two

components: mechanical tension and metabolic fatigue, which are both illustrated using color

gradients, with darker shades representing more contribution from each respective mechanism.

To calculate the percentage of muscle hypertrophy per training session (%PTS) in Figure1,

studies meeting the following criteria were used:

(a) Resistance exercise: a study that trained until failure in each setand comparedthe

muscle hypertrophic effects(1) between low-load (< 50%1RM) and high-load

(50-90 %1RM) resistance training or (2) between high-load (50-90 %1RM)and loads near

1RM (90-100% 1RM) or (3) between low-load (< 50 %1RM) resistance training with and
without BFR

(b) Aerobicexercise: studiesincluded inthree review papers by Ozaki et al. (2013, 2015a,


(c) Study population: sedentary or mild to moderately active adults

(d) Measurement: a study evaluating muscle hypertrophic effect at the whole muscle level

Resistance exercise until failure and typicalaerobic exercise

High external loads have primarily been recommended to maximize muscle hypertrophy.

The American College of Sports Medicine (ACSM) recommends lifting with approximately 70%

of a person’s one repetition maximum (1RM) for increasing muscle mass[5]. However, the use

of high external loads does not necessarily translate to greater muscle hypertrophy. For

example, Schmidtbleicher and Buehrle(1987) showed greater increases for cross-sectional area

(CSA) of the triceps brachii muscle for a group that trained with 3 sets of 12 repetitions at 70%

1RM compared with a group that trained with 7 sets of 1-3 repetitions at 90-100%1RM[13].

Although differences in exercise volume may explain a portion of this difference, the decreased

metabolic fatigue resulting from too short of an exercise duration may also contribute to this

differential hypertrophic response between groups.

Interestingly, recent studies have shown that low-load resistance training induces
comparable hypertrophy to that of high-load resistance training when each set is performed

until failure. For example, Mitchell et al. (2012) compared muscle hypertrophic effects between

low- and high-load resistance training for the following 3 groups: 1 set or 3 sets × 80% 1RM to

failure, and 3 sets × 30% 1RM to failure[6]. After 10 weeks of training consisting of 3 sessions

per week, the muscle hypertrophic response was similar between the 3 sets × 30% 1RM and

the 3 sets × 80% 1RM groups andtended to be lowest following1 set × 80% 1RM (though not

significantly lower). Although greater repetitions are required with lower loads to reach failure,

failure within each set typically occurs within a minute and is likely attributable to the

accumulation of metabolites.This accumulation of metabolites within the muscle may

compensate for the smaller mechanical stress, however, there is likely a point at which the load

may be too low to elicit marked muscle hypertrophy. For example, with external loads less than

20-30% of maximum strength, it may become difficult to maximize peripheral fatigue in a brief

bout of exercise[14-16]. To our knowledge, there is no study comparing the hypertrophic

effects between low-load (30-40% 1RM) and very low load (10-20% 1RM) resistance exercise,

thus this may warrant further work.

Aerobic exercise such as cycling and walking have also been shown to stimulate muscle

growth to varying magnitudesfor limited muscles (working muscles) or age groups

[9,10].Mikkola et al. compared thehypertrophic effect between high-load resistance training

(~80%1RM) and cycling (exercise intensity from aerobic to anaerobic threshold)[17]. As a

result, muscle CSA of the quadriceps femoris significantly increased for thecycle training group

(2%) after a21 week training program (2 days per week), though the hypertrophic effect was

lower compared with thehigh-load resistance training group (6%). The previous studies have

demonstrated that peak muscular activation (normalized by EMG recorded during MVC

(%MVC)) duringcycling was about 50%MVC in vastus lateralis and medialis muscles[18],

whereasthe average %MVC was approximately 30 % in vastus lateralismuscle[19].These

studiesimply that cycle training is capable of inducing muscle hypertrophy, but at slower

ratesandto lower magnitudes compared tohighload resistance training.This lower magnitude

may be due to the fact that the muscles are unlikely to be worked to, or near, failure during

continuous cycling at a moderate intensity. Thus, cycling at this intensity would fail to maximize

metabolic fatigue and suggests that perhaps cycle training performed to, or near, failure at

higher intensities may be more useful for stimulating growth.

On the other hand, Kubo et al. found that muscle thickness increased significantly for the

knee flexors and dorsi flexors following 6 months of walk training (45.0 ± 15.6 min/day, 5.4 ±

1.1 days/week) in sedentary, or mild to moderately active adults [20].As shown in

Figure1A, %PTSappears to be lower in walking compared with cycling. This may be because

both mechanical tension and metabolic fatigue are lower during walking than during cycling:
peak muscular activation (%MVC) of the vastus lateralis and vastus medialis during walking is

less than one quarter of the during cycling [18] anda bout of walking, unlike cycling, failed to

present the acute increase in muscle size[21]. This acute change is considered an indirect

measure of muscle cell swelling, which is likely due to a fluid shift form the plasma into the

muscle cell although the possibility of the increased muscle size resulting from just a blood

pooling and/or an increase in interstitial fluid cannot be completely ruled out[22,23]. Muscle

cell swelling may be one of factors shifting the protein balance towards anabolism[23,24].

Muscle protein metabolism following resistance and aerobic exercises

A prolonged shift of muscle protein turnover towards synthesis rather than

breakdown results in skeletal muscle hypertrophy [25]. Burd et al. (2010) compared muscle

protein synthesis induced by 4 sets of leg extension exercise between the following 3

conditions: 1) 90% 1RM until failure, 2) 30% 1RM with work output matched with that of 90%

1RM exercise, 3)30% 1RM until failure in each set.The rate of myofibrillar protein synthesis of

condition2 was approximately one half of that observed following condition 1, whereas it was

similar between condition 1 and 3[26].Greater metabolic fatigue with lower load resistance

exercise may compensate for the lower mechanical tension. The development of metabolic

stress may trigger the rate of muscle protein synthesis through activation of anabolic and/or
attenuationof catabolic signaling pathways[24].Although the muscle hypertrophic effects

seems to decreaseas exercise intensities near 1RM, it is unclear whether the rate of muscle

protein synthesis following resistance exercise at >90% 1RM is lower than that of resistance

exercise at ≤90% 1RM.

Similar to resistance exercise, aerobic exercise is effective in activating

anabolic[27,28] and/or attenuatingcatabolic[29] signaling pathways,and increasing muscle

protein synthesis[29]. However, the magnitude of these responses may be lower with aerobic

exercise than that observed with resistance exercise. For example, an elevated phosphorylation

of ribosomal protein S6 kinase was observed immediately after both cycle and resistance

exercise, but, after 4 h,remained elevated only in the resistance exercise group. Further, the

increase inmyofibrillar protein synthesis over the 4 hour post exercise period was only

stimulated following resistance exercise[27]. These findings may account for the lower

hypertrophic effect with aerobic exercise compared to resistance exercise.

Resistance and aerobic exercise combined with blood flow restriction

The mechanisms underlying adaptations to low load exercise to failure are

remarkable, but time consuming due toa greater work requirement. Similarly, aerobicexercise

is capable of inducing muscle growth, but at much slower rates, requiring a longer period
compared with resistance exercise. BFR accelerates the development of metabolic fatigue,

which enhances the hypertrophic effects and is considered an alternative method to combat

these potential temporal disadvantages.

Rececntly, Farup et al. (2015) investigated the muscular adaptations of young adults

following a low-load (40% 1RM) resistance training program, consisting of 4 sets/day of

unilateral dumbbell curls to failure × 3 days/week × 6 weeks with one arm combined with BFR,

and the other without BFR[30]. After the program, arm flexor muscle volume increased for

both limbs by similar degrees. Importantly, BFR resulted in less repetitionsper set, hence the

lower total exercise volume and training time for the entire training period, presumably due to

a faster rate of metabolic fatigue. This implies that metabolic fatigue, rather than exercise

volume, is crucial for muscle hypertrophy.Meanwhile, the other previous studies have shown

that resistance training at even 15-20% of maximal strength significantly induces muscle

hypertrophy when combined with BFR[31], but these studies lack a comparison with high load

resistance exercise and/or performing each set to failure, which would maximize metabolic

stress even under BFR condition. Thus, future research is needed to determine the lowest

intensity inBFR resistance exercise until failure in each set required formaintainingcomparable

hypertrophy to that of high load resistance traininguntil failure.

Given the advantage of BFR, it is plausible that the hypertrophic effect with
aerobicexercise can be enhanced, which would lead to shorter training period until significant

hypertrophy occurs. Ozaki et al. (2011) compared the effect of walking with and without BFR

on muscle size in older adults[11]. Subjects performed 20 minutes of walking at 45% heart rate

reserve, which was undertaken 4 days per week, for 10 weeks. The cross-sectional area (CSA)

of the thigh muscle significantly improved only in the group walking with BFR. Similarly, Abe et

al. (2010) compared the effects of an 8-week cycling program with and without BFR on muscle

size for young men and demonstrated that the CSA of thigh muscle increased only for

BFR-cycling[12]. Considering the findings of the walking and cycling studies without BFR, these

results clearly showed the potential of BFR in shortening the training period until significant

hypertrophy occurs. Given that aerobic exercise in combination with BFR is completed with a

low intensity, the muscle does not reach exhaustion and is thus unlikely to maximize the

metabolic fatigue induced by exercise. This lack of metabolic fatigue may explain why the

hypertrophic effect of aerobic exercise in combination with BFR is less than that observed with

low load resistance exercise in combination with BFR.

Muscle protein metabolismfollowingresistance and aerobic exercise combined with blood

flow restriction

As with resistance exercise without BFR, low-load resistance training with

BFRstimulates muscle protein synthesis[32]through activation of anabolic[32] and attenuation

of catabolic[33] signaling pathways. Recently, we have shown that even walking with BFR also

activates anabolic signaling pathways[34], though these responses appear to be greater for BFR

resistance exercise than for BFR walking. The phosphorylation of several selected proteins in

both mechanistic target of rapamycin and mitogen-activated protein kinase (MAPK) signaling

pathways increased 3h after a bout of low-load resistance exercise with BFR[32,35], whereas

BFR-walk stimulated the phosphorylation of only two selected proteins in MAPK signaling

pathway[34]. These findings appear to be consistent with the greater hypertrophic effect with

low-load BFR resistance exercise compared to that of BFR-walk. Because this notion resulted

from comparing previous studies published by different laboratories, future research should

confirm this using a within-subjects design.


This review providesevidence for the muscle hypertrophic response across a variety

of exercise modalities/intensities,whilst discussing the potential interaction between metabolic

and mechanical stimuli as mechanistic contributors to these adaptations. It is plausible that the

degree of contributions of both mechanical tension and metabolic fatigue determines the

exercise-induced hypertrophic effect as shown in Figure 1. However, it should be recognized

that exercise training is not always performed solely to induce muscle hypertrophy. For

example, the same hypertrophic effect would be observed between high-load and low-load

resistance training to failure, but strength gain would favor high-load in certain circumstances

due to the principle of specificity. For example, the group consistently training at a higher

percentage of their 1RM will perform better in a 1RM test compared to a group consistently

training at a lower percentage of their 1RM. Thus, if lifting maximal loads in a particular

exercise is of importance, one would need to have some degree of practice at lifting near

maximal loads in that particular exercise. Aerobic training induces less muscle hypertrophy

compared with resistance training, while producing greater improvements in aerobic capacity.

Understanding the characteristic of each training method and the mechanisms responsible for

the training effects will help in assigning the most suitable training program based on an

individuals goals and needs.

Conflicts of Interest

The authors report no conflict of interest.


This study was not supported by any funding.


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Figure Legend

Figure1A (traditional exercise) and Figure 1B (Blood Flow Restriction) illustrate the relationship

between muscle growth, exercise load, and the degree of contribution of mechanical tension

and metabolic fatigue.

The green and orange color gradients demonstrate the relative contributions of mechanical

tension and metabolic fatigue for inducing muscle hypertrophy. The orange color gradient

shows potential metabolic fatigue for each exercise load. The black color gradients

demonstrate strength of evidence. The black line shows the potential hypertrophic effect for

each exercise load. These figures are drawn based on hypertrophic effect at the whole muscle

level in studies employing sedentary, or mild to moderately active adults for relatively short

periods (cardiovascular exercise: ~6 months, resistance exercise: ~12 weeks) of time.

HL: High-Load, LL: Low-Load, BFR: Blood Flow Restriction in working muscles, MVIC: Maximum

Voluntary Isometric Contraction, 1RM: One Repetition Maximum, %PTS: % per training session
Conflicts of Interest

The authors report no conflict of interest.