Medical Hypotheses 88 (2016) 22–26

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Muscle growth across a variety of exercise modalities and intensities:

Contributions of mechanical and metabolic stimuli
Hayao Ozaki a,⇑, Jeremy P. Loenneke b, Samuel L. Buckner b, Takashi Abe c
a
School of Health and Sport Sciences, Juntendo University, Inzai, Chiba 270-1695, Japan
b
Department of Health, Exercise Science, and Recreation Management, Kevser Ermin Applied Physiology Laboratory, School of Applied Sciences, The University of
Mississippi, University, MS 38677, USA
c
National Institute of Fitness and Sports in Kanoya, Kanoya, Kagoshima 891-2393, Japan

a r t i c l e i n f o a b s t r a c t

Article history: This paper reviews the existing evidence for the potential contribution of metabolic and mechanical stim-
Received 8 October 2015 uli to muscle growth in response to a variety of exercise modalities and intensities. Recent research has
Accepted 29 December 2015 demonstrated that low-load resistance training can elicit comparable hypertrophy to that of high-load
resistance training when 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 stimuli are primary
mechanisms for muscle hypertrophy and the degree of contributions of both stimuli determines the
exercise-induced muscle hypertrophy.
Ó 2016 Elsevier Ltd. All rights reserved.

Introduction
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, strate-
gies 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 hyper-
trophy 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
⇑ Corresponding author at: School of Health and Sports Science, Juntendo
University, 1-1 Hirakagakuendai, Inzai, Chiba, Japan. Tel.: +81 47698 1001; fax:
+81 47698 1030.
E-mail address: ozaki.hayao@gmail.com (H. Ozaki).
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 dis-
cuss the potential interaction between metabolic and mechanical
stimuli.
Procedure for making figure
Fig. 1 displays the relationship between the training-induced
muscular hypertrophic response to resistance exercise until failure
or typical aerobic exercise (Fig. 1A), as well as during resistance or
aerobic exercise with BFR (Fig. 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.

http://dx.doi.org/10.1016/j.mehy.2015.12.026
0306-9877/Ó 2016 Elsevier Ltd. All rights reserved.
 H. Ozaki et al. / Medical Hypotheses 88 (2016) 22–26 23

Fig. 1. A (traditional exercise) and B (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.

To calculate the percentage of muscle hypertrophy per training (d) Measurement: a study evaluating muscle hypertrophic
session (%PTS) in Fig. 1, studies meeting the following criteria were effect at the whole muscle level.
used:

(a) Resistance exercise: a study that trained until failure in each
set and compared the 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) Aerobic exercise: studies included in three review papers by
Ozaki et al. (2013, 2015) [8–10].
(c) Study population: sedentary or mild to moderately active
adults.
Resistance exercise until failure and typical aerobic 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
24 H. Ozaki et al. / Medical Hypotheses 88 (2016) 22–26
[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 differ-
ential hypertrophic response between groups.
Interestingly, recent studies have shown that low-load resis-
tance 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 fol-
lowing 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 sim-
ilar between the 3 sets  30% 1RM and the 3 sets  80% 1RM groups
and tended to be lowest following 1 set  80% 1RM (though not sig-
nificantly 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 knowl-
edge, 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 magnitudes for lim-
ited muscles (working muscles) or age groups [9,10]. Mikkola et al.
compared the hypertrophic 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 quadri-
ceps femoris significantly increased for the cycle training group
(2%) after a 21 week training program (2 days per week), though
the hypertrophic effect was lower compared with the high-load
resistance training group (6%). The previous studies have demon-
strated that peak muscular activation (normalized by EMG
recorded during MVC (%MVC)) during cycling was about 50%
MVC in vastus lateralis and medialis muscles [18], whereas the
average %MVC was approximately 30% in vastus lateralis muscle
[19]. These studies imply that cycle training is capable of inducing
muscle hypertrophy, but at slower rates and to lower magnitudes
compared to high load 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 per-
formed 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 follow-
ing 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 Fig. 1A, %PTS appears 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] and a bout of walking, unlike cycling, failed to present
the acute increase in muscle size [21]. This acute change is consid-
ered 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 toward anabolism [23,24].
Muscle protein metabolism following resistance and aerobic
exercises
A prolonged shift of muscle protein turnover toward 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 condi-
tions: (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 condition 2
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 com-
pensate for the lower mechanical tension. The development of
metabolic stress may trigger the rate of muscle protein synthesis
through activation of anabolic and/or attenuation of catabolic sig-
naling pathways [24]. Although the muscle hypertrophic effects
seems to decrease as 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
690% 1RM.
Similar to resistance exercise, aerobic exercise is effective in
activating anabolic [27,28] and/or attenuating catabolic [29] sig-
naling 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 in myofibrillar protein
synthesis over the 4 h post exercise period was only stimulated fol-
lowing resistance exercise [27]. These findings may account for the
lower hypertrophic effect with aerobic exercise compared to resis-
tance 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 to a greater work
requirement. Similarly, aerobic exercise is capable of inducing
muscle growth, but at much slower rates, requiring a longer period
compared with resistance exercise. BFR accelerates the develop-
ment of metabolic fatigue, which enhances the hypertrophic
effects and is considered an alternative method to combat these
potential temporal disadvantages.
Recently, Farup et al. (2015) investigated the muscular adapta-
tions 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 repetitions per set, hence the
lower total exercise volume and training time for the entire train-
ing 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
in BFR resistance exercise until failure in each set required for
maintaining comparable hypertrophy to that of high load resis-
tance training until failure.
 H. Ozaki et al. / Medical Hypotheses 88 (2016) 22–26
Given the advantage of BFR, it is plausible that the hypertrophic
effect with aerobic exercise 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 min 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 combi-
nation with BFR is less than that observed with low load resistance
exercise in combination with BFR.
Muscle protein metabolism following resistance and aerobic
exercise combined with blood flow restriction
As with resistance exercise without BFR, low-load resistance
training with BFR stimulates muscle protein synthesis [32] through
activation of anabolic [32] and attenuation of catabolic [33] signal-
ing 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 3 h after a
bout of low-load resistance exercise with BFR [32,35], whereas
BFR-walk stimulated the phosphorylation of only two selected pro-
teins 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 dif-
ferent laboratories, future research should confirm this using a
within-subjects design.
Summary
This review provides evidence 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 adapta-
tions. It is plausible that the degree of contributions of both
mechanical tension and metabolic fatigue determines the
exercise-induced hypertrophic effect as shown in Fig. 1. However,
it should be recognized that exercise training is not always per-
formed 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 com-
pared 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 resis-
tance training, while producing greater improvements in aerobic
25
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 individ-
uals goals and needs.
Conflicts of interest
The authors report no conflict of interest.
Acknowledgement
This study was not supported by any funding.
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