Journal of
Cellular
Physiology
2
~
JASON CHOLEWA,1 LUCAS GUIMARAES-FERREIRA,
TAMIRIS DA SILVA TEIXEIRA,3
3 ALICE LODETTI,3
MARSHALL ALAN NAIMO,4 XIA ZHI,5,6 RAFAELE BIS DAL PONTE DE SA,
MAYARA QUADROS CARDOZO,3 AND NELO EIDY ZANCHI3*
1
Department of Kinesiology Recreation and Sport Studies, Coastal Carolina University, Conway, South Carolina
Laboratory of Experimental Physiology and Biochemistry, Center of Physical Education and Sports,
Federal University of Espirito Santo, Vitoria, Brazil
Postgraduate Program in Health Sciences, Health Sciences Unit, Universidade do Extremo Sul Catarinense, Criciuma, Brazil
Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, West Virginia
Exercise Physiology and Biochemistry Laboratory, College of Physical Education, Jinggangshan University, Jinggangshan, PR, China
Exercise Physiology Laboratory, Department of Exercise Physiology, Beijing Sport University, Beijing, PR, China
Human muscle hypertrophy brought about by voluntary exercise in laboratorial conditions is the most common way to study resistance
exercise training, especially because of its reliability, stimulus control and easy application to resistance training exercise sessions at fitness
centers. However, because of the complexity of blood factors and organs involved, invasive data is difficult to obtain in human exercise
training studies due to the integration of several organs, including adipose tissue, liver, brain and skeletal muscle. In contrast, studying
skeletal muscle remodeling in animal models are easier to perform as the organs can be easily obtained after euthanasia; however, not all
models of resistance training in animals displays a robust capacity to hypertrophy the desired muscle. Moreover, some models of resistance
training rely on voluntary effort, which complicates the results observed when animal models are employed since voluntary capacity is
something theoretically impossible to measure in rodents. With this information in mind, we will review the modalities used to simulate
resistance training in animals in order to present to investigators the benefits and risks of different animal models capable to provoke
skeletal muscle hypertrophy. Our second objective is to help investigators analyze and select the experimental resistance training model
that best promotes the research question and desired endpoints.
J. Cell. Physiol. 229: 11481156, 2014. 2013 Wiley Periodicals, Inc.
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RF, rectus femoris; EDL, extensor digitorum longus; SOL, soleus; FHL, flexor hallucis longus; PLA, plantaris; GAS, gastrocnemius; CSA, cross-sectional area.
2012
2002
Scheffer et al.
Fluckey et al.
12 weeks
4 weeks
Alternate days
43 steps
5 weeks
8 weeks
8 weeks
Every 2 days
80
1.1 m
2012
2003
2004
Dela Cruz et al.
Wirth et al.
Hornberger
2009
1999
Zanchi et al.
Tamaki et al.
15 jump sessions
1215
1
8 weeks
36 weeks
2004
1988
Lee et al.
Klitgaard et al.
85
1215
26 weeks
4 days/week
1998
Duncan et al.
40 cm
Vertical
Increase in RF weight
8 weeks
5 days/week
90
40 cm
Technical
Year
Author
Size/height
Angulation
Sessions/weeks
Training
period
20
Series/day
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Year
Goldberg et al.
Goldberg et al.
Wong and Booth
1968
1975
1988
1999
Goldspink
1999
Technical
Period
Estimulus
6 days
14 days
16 weeks
Walk
Walk
Electric external load
6 weeks
Electric
4 days
Electric
2005
Venous occlusion
2006
Electrical stimulation
2 weeks
6 days
Isometric contractions
EDL, extensor digitorum longus; SOL, soleus; TA, tibialis anterior; flexor hallucis longus; PLA, plantaris; GAS, gastrocnemius.
Fig. 1. Progression of the development of resistance training models in Rodents (19682012). (A) Surgical ablation; (B) Tenotomy; (C)
voluntary plantar extension; (D) 85 weighted ladder climb; (E) non-voluntary hind-limb extension; (F) passive stretch; (G) 90 weighted ladder
climb; (H) electric stimulated squat; (I) modified non-voluntary hind-limb extension; (J) modified flywheel with hind-limb suspension; (K)
operantly conditioned squat; (L) modified operantly conditioned squat. (M) jumping submersed in water with overload. Adapted by the
authors.
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spaceflight (gravitational unloading) via hind limb suspension. Under this condition of atrophy, isometric-based
resistance training models capable of producing robust
hypertrophy under gravitational conditions have failed to
induce hypertrophy or counteract atrophy (Haddad
et al., 2006). It is possible that this resistance training
model may have attenuated the loss of muscle mass under a
gravitational model of atrophy (i.e., administration of
rapamyacin). On the other hand, it is well established in
the literature that dynamic resistance training plus
nutritional support (mainly proteins containing high biological value and leucine) are capable of robustly activating
protein synthesis pathways (Phillips, 2011) and counteracting unloading-induced loss of muscle mass as demonstrated by Fluckey et al. (2002). When considering the
catabolic state as generated by glucocorticoids and diabetes
mellitus, we demonstrated that resistance training is capable
of counteracting the loss of muscle mass (Nicastro
et al., 2012a). Although further research in humans is
needed to describe the hormonal milieu and muscle
activation in response to daily living activities in humans
with atrophic disease, our model provides researchers with
a greater degree of control over the variables involved in
resistance training, and can be used to study the effects of
resistance training on atrophy during conditions of
gravitational unloading and glucocorticoid catabolism.
In example of how these factors may affect investigation
outcomes, Miyazaki et al. (2011) utilized the synergistic
ablation surgery to investigate the involvement of ERK/MERK
pathways and the well-known Akt/mTOR/P70S6K pathways of
protein synthesis initiation in the muscle hypertrophy
phenomena. Using the synergist ablation model of muscle
hypertrophy, early and late periods of muscle adaption were
examined. Specifically, they measured these adaptations in a
model of form follows signaling function observing plantaris
hypertrophy weight from day 0 to day 10 on a daily basis.
Miyazaki et al. (2011) demonstrated that Akt phosphorylation
(Ser 473 or Thr 308) was not activated until days 23, whereas
P70S6K (Ser 389, Thr 421/424) and ribosomal protein (RPS6
Ser 235236) where highly phosphorylated during the entire
hypertrophy process. Of note, this delay in the classical Akt/
mTOR activation was accompanied by a rapid and prolonged
MEK 1 and 2 (Ser 217/221) activation. The same pattern was
observed in ERK 1 and 2 (Thr 221 and 224). Importantly, this
divergence utilizing a well-recognized animal muscle
hypertrophy model demonstrated parallel pathways, one
activated early and one later, that both phosphorylated the RP6
protein culminating in increased protein synthesis. In the early
pathway ribosomal kinases phosphorylated the RP6 in the Ser
235/236 residue. Following the late pathways, RPS6 was
phosphorylated in the residues Ser 240/244. This study
demonstrates the importance of matching expected outcomes
within the research question to the resistance training model
employed. If Miyazaki et al. (2011) had utilized a model
requiring a longer duration of conditioning or training to induce
muscle remodeling (i.e., the squat model) these novel
discoveries may not have been made. Thus, investigators need
to be aware of these particular attributes to resistance training
models when investigating molecular signaling pathways,
ergogenic aids, and mechanical tensions and muscle
remodeling.
Conclusion
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