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4 Appl Physiol 127; 806-815, 2019.
Fit published Jaly 3, 2019; dei10.1152pplphysol 00380.2019
RESEARCH ARTICLE | Translational Control of Muscle Mass
Myofibrillar protein synthesis and muscle hypertrophy individualized
responses to systematically changing resistance training variables in trained
young men
Felipe Damas,' Vitor Angleri,! Stuart
Natalia Santanielo,' Samuel D. Soligon,
and Cleiton A. Libardi!
Phillips,? Oliver C. Witard,? Carlos Ugrinowitsch,*
iz A. R. Costa,! Manoel E, Lixandro,* Miguel S. Conc
'MUSCULAB-Laboratory of Neuromuscular Adaptations to Resistance Training, Department of Physical Education, Federal
University of Sao Carlos, Sd0 Carlos, Brazil: *Department of Kinesiology, McMaster University, Hamilton, ON, Canada:
Centre for Human and Applied Physiological Sciences, School of Basie and Medical Biosciences, Faculty of Life Sciences
‘and Medicine, King’s College London, London, United Kingdom: and “School of Physical Education and Sport, University of
‘So Paulo, So Paulo, Brazil
Submited 22 May 2019: accepted in final form 28 June 2019
Damas F, Angleri V, Phillips SM, Witard OC, Ugrinowitsch C,
Santanielo N, Soligon SD, Costa LA, Lixandrio ME, Concelgio
MS, Libardi CA. Myofbrillar protein synthesis and muscle hype
trophy individualized responses to systematically changing resistance
training variables in trained young men. J Appl Physiol 127: 806—
815, 2019, First published July 3, 2019: do:10.1152appIphysil
(00350.2019.—The manipulation of resistance training (RT) variables
is used among athletes, recreational exercisers, and compromised
populations (e.., elderly) attempting to potentiate muscle hyperto-
phy. However, itis unknown whether an individual's inherent pre-
disposition dictates the RTsinduced muscle hypertrophic response.
Resistancestrained young [26 @) y] men (n = 20) performed 8 wk
unilateral RT (2 times/wk), with 1 leg randomly assigned to a standard
progressive RT [control (CON)] and the contralateral leg to variable
RT (VAR; modulating exercise load, volume, contraction type, and
interset rest interval). The VAR leg completed all 4 RT variations
‘every 2 wk, Bilateral vastus lateralis cross-sectional area (CSA) was
measured, pre-and post-RT and acute integrated myofibrillar protein
synthesis (MyoPS) rates were assessed a est and over 48 h following
the final RT session, Muscle CSA increase was similar between CON
and VAR (P > 0.05), despite higher total taining volume (TTV) in
VAR (P< 0.05). The 0-48-h integrated MyoPS increase postexer-
cise was slightly greater for VAR than CON (P < 0.05), All partic-
ipants were considered “responders” to RT. although none benefited
to a greater extent from a specific protocol. Between-subjects vari-
ability (MyoPS, 3.30%; CSA, 37.8%) was 40-fold greater than the
intrasubject (between legs) variability (MyoPS, 0.08%; CSA, 0.9%).
‘The higher TTV and greater MyoPS response in VAR did-not
teanslate to a greater muscle hypertrophic response. Manipulating
‘common RT variables elicited similar muscle hypertrophy’ than a
standard progressive RT. program in trained young men. Intrinsic
individual factors are key determinants of the MyoPS and change in
muscle CSA compared with extrinsic manipulation of common RT
variables
NEW & NOTEWORTHY Systematically manipulating resistance
taining (RT) variables during RT augments the stimulation of myo
‘Aires for reprint requests and other correspondence. C. A, Libari
MUSCULAB-Lhortory of Newomuscular Adaptations to Resistance Tri
ing, Dep. of Physical Education, Federal Univ, of Sao Carlos, UFSCar, Rod.
‘Washington Laz, km 235 — SP 310, CEP 13365-905, Sio Carlos, SP, Braz
(eons indi utah,
06
§750-1581/19 Copyright © 2019 the American Physiological Society
Absilar protein synthesis (MyoPS) and traning volume but fails to
potentiate muscle hypertrophy compared with standard progressive
RT. Any modest further MyoPS increase and higher training volumes
do not reflect in a greater hypertrophic response. Between-subject
variability was 40-fold_ greater than the variability promoted. by
extrinsic manipulation of RT variables, indicating that individual
intrinsic factors are stronger determinants of the hypertrophic re-
sponse.
biological predisposition; individual responses; muscle protein syn
thesis: resistance exercise; taining protocol
INTRODUCTION
‘Skeletal muscle tissue plays an important role in maintaining,
‘metabolic health, reducing disease risk, and improving athletic
performance (7, 44). A crucial nonpharmacological stimulus
for maintaining or increasing muscle mass is the practice of
resistance training (RT). In this regard, an acute out of
resistance exercise is well established to promote the stimula-
tion of myofibrillar protein synthesis (MyoPS), which if prac-
ticed over time, results in the accretion of muscle protein and
increase in muscle cross-sectional area (CSA) (18). To poten-
tiate the muscle hypertrophic response, reputable strength and
conditioning guidelines advise periodic changes in RT compo-
sition to avoid a plateau in skeletal muscle adaptations, espe-
cially in a more trained state (1, 21). These changes involve the
manipulation of common RT variables such as exercise load,
training volume, muscle contraction type (e.g. isolated eccen=
tric or concentric contractions), inteset rest interval, etc, How
ever, itis unknown whether such training-specific manipula-
tions are effective in potentiating MyoPS and muscle hyper-
‘wophy in resistance-trained men.
A large body of literature demonstrates that manipulating
fone single RT variable at a time results in a similar acute
postexercise stimulation of MyoPS and muscle hypertrophic
response to RT when each exercise set is performed until, or
close to, concentri failure (3, 8, 30-33, 36, 38, 40). Exercising
Up 10, oF close to, concentric failure seems to promote a
substantial increase in MyoPS and muscle hypertrophy (11, 12,
pare japon MUSCLE PROTEIN SYNTHESIS AND HYPERTROPHY IN TRAINED MEN
32, 39). However, to date no study has compared the MyoPS.
responses to acute exercise and the muscle hypertrophy’ to a
systematic and constant manipulation of several RT variables
throughout traning sessions, as opposed to modulating each
variable independently, when all training modulations are per-
formed up to or close to concentre failure.
Despite a high degree of eifort being exerted in each RT
session, theoretically each individual willbe limited to their
inherent capacity to respond to RT-indueed muscle hyperto-
phy. We recently demonstrated that manipulating the weekly
frequency of RT in untrained subjects modulated the intrasu-
bject response of muscle hypertrophy, with 95% of the part
ipants defined as “responders” after the intervention (15). In
addition, some, but not all, participants benetited more from a
specific RT frequency (15). Nevertheless itis unknown if a
systematic manipulation of various RT variables through ses-
sions in trained subjects could indeed modulate the intrasubject
muscle hypertrophic responses to RT. Besides the intrasubject
response, we (15) and several thers (4, 6. 14, 26, 34) have
reported a large between-subjects variability in RT-induced
muscle hypertrophy irespectve ofthe RT program performed
‘These observations suggest that the muscle hypertrophic re~
sponse to various RT manipulations is partially dependent on
the individual's intrinsic predisposition to respond to RT.
However, no study has determined whether intrinsic individual
factors play a more prominent role in determining RT-induced
muscle hypertrophy than modifiable extrinsic RT characters
tes,
The aim of this study was 10 investigate the impact of
systematically manipulating RT variables on the individual
RT-induced muscle hypertrophic response when training ses-
sions are performed with high-level effort in esistance-trained
young men. To address this aim, we measured changes in
imuscle CSA in response to an 8-wk unilateral RT model with
all sets performed to (or close 1) concentric failure, in which
the control leg performed a standard progressive RT protocol
(CON), whereas the contralateral leg. performed a. variable
(VAR; modulating exercise load, volume, contraction type,
and interset rest interval each session) RT protocol. To provide
mechanistic information and explore individual variations in
the acute metabolic response to distint RT protocols that could
be missed using a chronic assessment of muscle CSA, we also
utilized the deuterium oxide racer methodology to measure the
807
exercise following both RT protocols. We hypothesized 1) that
at a group level, CON and VAR RT protocols would elicit a
similar muscle hypertrophic response: 2) that at an individual
level, a high number of responders to RT and a low intrasubject
variability between legs, with some participants (not all) re-
sponding better to one specific RT protocol, consistent with our
previous observation when modulating weekly RT frequency
(15); 3) a large between-subjects variability in the muscle
hypertrophic response irrespective of RT protocol performed:
and 4) that integrative MyoPS rates would correspond with
changes in muscle CSA following RT but with small individual
differences between RT protocols because of the sensitivity of
this measurement
METHODS
Participants, The Human Research Ethies Committe of the local
university approved the study (no. 2.236.596). Experimental proce-
dures and associated risks were explained to each participant, who
‘provided written and informed consent before participation. All pro
‘cedures performed herein Were in aecordance with the ethical stan-
dards ofthe institutional and national research committe and with the
1964 Helsinki Declaration and its later amendments or comparable
ethical standards
Healthy resistance-rained young men (1 = 20; mean (SD), age: 26,
(@) yr, body mass index: 25.6 (2.1) kg/m’, and previous RT. experi-
cence: 2.5 (1) yr] were reerited for the study. The trained subject ia
the current study had krger vastus lateralis muscle CSA at training
‘onset and greater muscle strength compared with untrained subjects
from our previous studies (8,19). As inclusionary criteria, the paric-
ipants had to be free from musculoskeletal disorders that would
prevent adequate performance of the RT protocols and should not use
Anabolic steroids
General design. We used a within-subjects unilateral study design
[totaling 40 experimental units (Tegs)] that involved both chronic Fig.
1A) and acute (Fig. 1B) experimental tals. All participants completed
familiarization session with al training protocols before RT onset.
Afierwards, they performed twice weekly unilateral RT over 8 wk,
‘with one leg randomly assigned to a standard progressive contol RT
(CON) protocol and the contralateral leg allocated to a variable RT
(VAR) protocol that systematically and sequentially (Le., every ses-
sion) modified the following exercise-elated variables at each RT
session: 1) load (VAR-load), 2) volume (number of sets: VAR-seIs)
3) type of muscle contraction (isolated eccentric contractions: VAR"
‘ece), and 4) interset rest interval (VAR-test) (see Full descriptions of
RT protocols below). Participants completed all four VAR conditions
in a counterbalanced randomized manner every 2 wk of the 8-wk RT
[A tei oo B =
=a fe bk em
sag aR Mote
Soe apes htt
sph + +—__] "0
aoe i am Pott tt
Fig. | Chron (A) and acute (8) experimental designs. Double arrows indicate bilateral muscle biopsies. CON, contol resistance taining [8 se (4 of leg ress
and 4of lg extension) of 912 reps to concentric falue/2-min est): CSA. cross-sectional are: DsO, deuterium oxide: RE, resistance exercise RT, ressance
Training: VAR, vriahle resistance taining ['.” VAR-load: 8 sts (4 of leg press and 4 of leg extension) of
te (6 of leg pres nd 6 of leg extension) of 9-12 reps to concentric fale/2-mi res c VARCee: 8st (4 of leg pres aid tof eg extension)
VAR ts
30 rps to concentric Failure
‘of 10 eccentric contractions at 110% ofthe lad used in CON ieg/>-min rest and “’-VAReTest 8 sels (4 of leg press and 4 of leg extension) of 9-12 reps 0
‘concent flurel-min ret
4 Appl Physi «di 0.1152j apple 003502019 + www japon 808
period. Thus, each participant performed each VAR condition four
limes during the $-wk training program. Leg dominance was coun
terhalanced between protocols, ie. 10 dominant and 10 nondominant
legs in CON and VAR. Before and after the 8-wk RT period (3 days
ator the last RT session), bilateral vastus lateralis CSAs were mea-
sured using an ultrsound imaging fting technique (28). The aceu-
mulated total taining, volume (TTV; sets X repetitions % load) pet=
formed by CON and VAR legs over the S-wk RT. period was
calculated. For the VAR-ece, each eccentric contraction Was consid-
fered one repetition for the TTV calculation.
‘After week 8 of RT. participants underwent an acute metabolic tril
to measure integrated rates of MyoPS at rest and over 48 hin response
toa single RT session, Each participant ingested 2 150-mL bolus of
70% deuterium oxide (D:0) 48 h hefore (48 h) the acute RT session
(17th overall RT session, performed 4 days after the last RT session),
saliva samples (-2 mL) were collected daily (fom ~48 h to 48 h after
the acute RT session), and bilateral vastus lateralis biopsies (~S0 mg)
were obtained immediately heore (Oh) and 24h and 48 hafter the RT
session, The integrated response of MyoPS was measured atthe end
‘of the RT program to ensure participants were accustomed to the
‘assigned exercise stimulus. We have previously shown that muscle
‘damage elicited by unaccustomed RT precludes the relationship
between MyoPS and muscle hypertrophy (18), and even trained
subjects can experience a degree of muscle damage. especially if RT
involves isolated eccentric contractions (22) as per the VAR&c (see
below) inthe present study design. For the acute RT session, paric=
ipants performed the CON protocol with {leg (r= 20. using the same
leg they used in the chronic design) and 1 of the 4 VAR conditions
(andomized among participants but reaching n = 5 per condition)
with the contralateral leg. After every RT session, including the 17th,
participants ingested 30 g of isolated whey protein to stimulate a
maximal MyoPS response to each RT bout (43).
Vastus lateralis CSA. To measure muscle hypertrophy, we ans-
lyzed changes in vastus lateralis CSA Following procedires deseribed
previously (28). In short, ultrasound (B-mode, 7.5-MH? linear array
probe, Samsung MySono U6, Sio Paulo, Brazil) sequential images
(from middle-te-lateal direetion position) of the vastus lateralis
muscle were captured while participants relaxed in a supine postion
‘Thereafter, images were fed together by reconstructing the vastus
lateralis CSA, which was measured using computerized planimetey.
‘The typical err between 2 repeated measures performed on diferent
days and 72 h apart was 0-44 em? (1.4%)
Resistance training. The CON protocol consisted of 8 sets (4 sets
‘of unilateral leg press followed by 4 sets of unilateral leg extension
exercise) of 9-12 repetitions of resistance exercise to concentric
failure with a 2-min interset rest interval, Repetition range was
achieved by increasing or decreasing the Joad between sets as provi
‘ously described (19). Each session of the VAR protocol invelved one
‘ofthe following RT manipulations: 1) VAR-oad, 8 sets (4 of eg press
land 4 of leg extension) of 25-30 reps to concentric failure/2-min
interset rest interval: 2) VAR-sets, 12 set (6 of leg press and 6 of lez
extension) of 9-12 reps to concentric failure/2-min interset rest
interval: 3) VAR-cce, 8 sts (4 of leg press and 4 of leg extension) of
10 eoventsic contractions at 110% of the Toad used in the CON
Jeg/2-min interset rest interval and 4) VAR-rest, 8 ses (4 of leg press
and 4 of leg extension) of 9-12 reps to concentric failure/4-min
intorset rest interval.
Muscle biopsy. Biopsies of the vastus lateralis were performed
using the percutaneous muscle biopsy technique with suction under
local anesthesia (2-3 mL. of 1% Xylocaine (lignocaine). Approni-
mately 50mg musele tissue was dissected Tree from blood and
‘connective tissue in preparation for quantilying the rae of MyoPS.
After separation, issue samples were immediately frozen in liquid
nitrogen and stored at ~80-C until analysis,
Integrated mvofibrillar prowin fractional synthetic rate. MyoPS.
rate was assessed using te D:O ingestion bolus (150 mL. of 70%
:0, Cambridge Isotope Laboratories, Tewksbury, MA), combined
MUSCLE PROTEIN SYNTHESIS AND HYPERTROPHY IN TRAINED MEN
‘with collection of saliva samples (through gentle spitting into tube
to avoid bubbles) and muscle biopsies, as described previously (18).
Briefly, saliva samples were analyzed by cavity ring-lown spectros-
copy sing a Liquid Water Isotope Analyzer using an automated
injection systom (version 2 upgrade, Los Gatos Research, Mountain
View, CA) for deuterium enrichment (Metabolic Solutions, Nashua,
[NH). Samples were vortexed and spun at 8,000 revolutions/min to
remove any debris. The water phase of saliva was injected 6 times,
fand the average of the final Wiplicale measurements Was used for
analysis. Standard curves of known D:O enrichment were plotted
‘against calculated deuterium enrichments in saliva samples. Intr-run
precision was <2 delta per mil (parts per thousand}, and inter-un
precision was <3.5 delta per mil.
‘Approximately 50 mg of wet muscle tissue was used to measure
deuterium enrichment in myofibillar muscle protein. Fach muscle
sample was homogenized, collagen was removed by adding | mL. 0.3
M NaOH and heating at 50°C for 30 min, and free alanine was
obtained by adding 1 mL. of 1 M perchloric acid, Hydrolysis of the
‘myofibrillar protein was performed after the addition of | ml. Dowex
H resin (50.W 8-100, Sigma-Aldrich, wth 0.1 MHC and 1 mL.
TM HCI to trap released alanine from the protein, The protein was
hydrolyzed for 24 hat 100°C. Amino acids were eluted from the resi
using 2 mL of 3 N NHOH and evaporated to dryness, Alanine was
derivatized to its n-aceyl, n-propyl ester according to the protocol of
‘Merritt and Hayes (29), with slight modification. The carboxyl group
of alanine was esterified using 3 N HCVa-propanol, and the amino
‘roup of alanine Was esterified using 100 acetic anbydride and 100
HAL pyridine. Incorporation of deuterium into protein-bound alanine
‘was determined by gas chromatography (GC)-pyrolysis-IRMS with a
‘Thermo Finnigan Delta V IRMS coupled to & Thermo Trace GC Ul
with @ GC combustion interface IIT and Conflow IV (Metabolic
Solutions). The N-acetyl, n-propyl ester of “H-alanine was analyzed
using a splitess injection with CTC Pal autosampler (Iw) at an
injection emperature of 20°C and using a Zebron ZB-5 column of 30
'm X 0.25 mm 0.50 pm film. The GC oven was programmed with
an initial column temperature of 100°C witha 1 min hod, followed by
ramp of 10°C per min to 150°C and a final amp of 30°C per mi
to 340°C, Compounds eluting off the column were directed into the
pyrolysis reactor, heated at 1.450°C. and converted to hydrogen gas
‘with monitoring of masses 2 and 3. Alanine standards Were used to
‘monitor retention time, Standards of known isotopic abundance were
used to calibrate the insteument
Myofibrillar protein fractional synthetic rate (FSR) was deter.
mined using the following formula: fractional synthetic rate (%/
day) = [APE q)/(APE,) % 1 X 100, in which atom % excess
(APE)ao is the deuterium enrichment of protein-bound alanine,
‘APE, is the mean deuterium enrichment (in atom percent excess,
‘onected for the mean number of deuterium moieties incorporated
per alanine, 3.7) in total body water between the time points, and
1s the time between biopsies.
Statistical analysis. Data were normally distributed according (0
the D'Agostino and Pearson normality test. Weekly progression of
‘TTV was compared between CON and VAR using slopes and elev
tion comparisons Irom linear regression, Paired samples Fests Were
used to compare absolute muscle CSA at baseline, pre-to-post-RT
changes in muscle CSA, the 8-wk accumulated TTV. the 17th RT
session TTV, and 0—48°h integrated MyoPS values between CON
and VAR, A mixed model analysis was used compare absolute
values of muscle CSA and MyoPS rates, assuming time (pre and post
Toe muscle CSA; and rest, 24h, and 48 b for MyoPS) and group (CON
and VAR) as fixed factors and participants as a random factor. To
‘compare TTV and the integrated 0 48-h MyoPS response to the 17th
RT session separated by VAR conditions, a mixed model analysis was
‘conducted, with group (CON protocol and all 4 VAR conditions) set
fs fixed factor and participants as a random factor. In case of
Significant F-values in the mixed models, Tukey’s post hoe test was
used for pairwise comparisons. For intrasubjeet analyses, te follow
4 Appl Physi «di 0.1152j apple 003502019 + www japon MUSCLE PROTEIN SYNTHESIS AND HYPERTROPHY IN TRAINED MEN
A caw] © CON
= VAR
2 / Al
— nme
10000)
12345678 9 WRISTS
Weeks:
Fig. 2 Total traning volume [TTY
809
B 30000, :
Ean
© soa ae
CON VAR
ns (SE throughout every week of resistance training following contol (CON) and viable (VAR) protocols with slopes
{continous steaight ins) and 95% confidence intervals (pointed ines) (A and the S-wk accumulated TTY for CON ara VAR protocols (2). Bar re means,
and dvs represen individual responses. °Signifcamly different fam CON (P < 0.000)
ing criteria was stipulated: change in S¢CSA >2 typical errors (i.
2.86) from zero defined the participant as a “responder” (as opposed
to a “nonresponder") to the corresponding RT protocol (25). Addi
tionally if an individual showed a pre-to-postRT change in CSA
from CON to VAR >2 typical erors (ie. 2.8%), the participant was
deemed to have responded hetter to CON (or vice versa), but if the
difference was within 2 typical errors, the muscle hyperophic 1e-
sponse was considered to be not different between protocols (15)
etween-subjects variability was determined by the coefficient of
variation (CV; SD/mean in %) within each RT protocol (CON and
VAR) and by the Levene's test, Correlations analyses using Pearson's
product moment correlation were conducted to determine if muscle
hypertrophic outcomes could be predicted by other variable. Data are
means (SD) unless otherwise stated. Significance was set as P = 0.05.
RESULTS
Chronic results. Group analyses revealed that the progres-
sion of TTY throughout the RT program was similar between
CON and_VAR (slopes comparison, P = 0.819), but the
elevation (intercepts) of the linear regression lines was signif
antly greater in VAR (P < 0.0001, Fig. 2A). Accordingh
with the latter, the 8-wk accumulated TTV was significantly
greater in VAR than CON (P < 0.0001, Fig. 28),
Vastus lateralis CSA was similar between CON and VAR at
pre [CON pre: 34.2 (5.4) cm®, VAR pre: 33.6 (5.4) em’; P =
0.282], Both CON and VAR protocols promoted significant
increase in vastus lateralis CSA from pre- 0 post-RT [CON
post: 36.8 (5.9) cm’, VAR post: 36.1 (5.7) em’; time effect,
P< 0,001], but the increase was similar between protocols
(group and interaction effects, P > 0.05). The pre-to-post-RT
delta change in vastus lateralis CSA also was similar between
CON and VAR (P = 0.473, Fig. 3)
‘Al participants were considered “responders” (i.e, all re-
sponses were above 2.8% from 0) to CON in terms of RT-
induced muscle hypertrophy, with only one participant mar-
‘inally below the “responder threshold” following VAR (Fig
3). The iniraindividual analysis revealed that none of the
suibjects benefited more from CON or VAR, i... all differ-
ences in CSA % change between CON and VAR (or vice
versa) were within 2 typical errors [CON values minus VAR
values ranged from ~1.55% to 1.75%: mean (SD) = 0.91%
(0.51%)]. Between-subject variability (ce. imtersubjects within
each RT protocol) was high, with CVs of 37% and 38% for
CON and VAR, respectively. Thus, the between-subject vari-
ability was ~41,8-fold greater than the intrasubject variability.
Levene’s test showed that the between-subjects variability was
similar for CON and VAR protocols (P = 0.77)
‘Acute results. The TTY of the 17th RT session was greater
for VAR compared with CON [CON: 13,636 (2.860) kg. VAR’
15,191 (4,775) kg: P = 0.029]. Separated by VAR conditions,
the TTV of VAR-sets was higher than CON and all other VAR
conditions (P < 0.02)
Body water enrichment increased up to ~0.18% APE on day
1 and decayed linearly thereafter (7 = 0.997). Figure 4 dis-
plays the daily integrated rates of MyoPS at rest and 24 h and
48 halter the acute CON and VAR RT sessions separated by
each VAR condition, MyoPS rates increased from rest at 24 h
and 48 b for all protocols (time effects. P< 0.001, Fig. 4,
A-D). Only the comparison between protocol VAR-load and.
CON showed a significant group versus time interaction (P
0.007, Fig. 4A). Post hoe tests showed that both protocols
promoted MyoPS inereases from rest at 24 h (P< 0.001) and
only VAR-load at 48 h (P = 0.016). The inerease in MyoPS
promoted by VAR-load was greater than CON at 24 (P
0,008, Fig, 44). Additionally, a group effect was observed for
VAR-sets, demonstrating greater MyoPS values than CON
(P= (1042, Fig. 4B),
The integrated 0-48-h MyoPS increase was greater for
VAR compared with CON (P < 0.0001, Fig, 54). Separated by
VAR condition, only VAR-sets resulted in greater 0-48-h
‘MyoPS compared with CON (P = 0.0001, Fig. 5B). Intrain-
dividual analysis revealed that differences in the integrated
(0-48-h MyoPS increase between CON and VAR ranged from
=——_
Change in CSA (%)
4 =
7 os
c
‘CON VAR
Fig. 3. Changes in vastus lateralis crosesectional area (CSA) for contol
(CON) and variable (VAR) resistance training protocols with » ted line
Indicating the “cutoff tvesbold point (Le, 2.8) fr responsiveness, Bas ate
‘means, ad dts represent individ responses.
4 Appl Physi «di 0.1152j apple 003502019 + www japon 810
MUSCLE PROTEIN SYNTHESIS AND HYPERTROPHY IN TRAINED MEN
A Deon Bo ceo), + t
- oe . to, Evan
+ =
$4 $4
2 ww Ew
g g
oo oa
Ra in ‘s Rae 2 ‘a
Time Time
c con + + D acon : +
Bi vatec
a 20) Vat
gus = Sas
3 2
= 0 = vo
Fas Zs
oo oa
Wat 2h a Tae Ey ‘a
Time Time
Fig. 4. Daily integrated rates of myotiillae protein synthesis [MyoPS: means (SD)] a a rested condition (Rest) an over 48 bh in response to an acute bout of
resistance exereie ofthe cool protocol (CON) nd
respoctively- #Signiiandy dit
variable (VAR) condition (VARcIoad, VARssts, VARcocc, VARerex ce METHO0S for details A-D,
ent from Rest within each protocol (P = 0.0}. *Signicantly diffrent from CON within tne point (P= 0.008). #Min te
‘lect [24 hand 48 h significantly diferent (P — 0.001 fom Rest. *Msin group elect [VARs sigifantlyeiferent (P= 0.042) from CON}
0.01% t0 0.21% {mean (SD) = 0.08% (0.05%)]. However,
the between-subjects CV for the (48-h MyoPS increase was
higher: ~3.5% for CON and ~3.1% for VAR. Thus, the be-
‘wween-subject variability was ~41 3-fold greater than the intra-
subject variability for MyoPS responses to acute exercise.
imilarly to muscle CSA results, Levene’s test showed that the
between-subjects variability for MyoPS responses was similar
for CON and VAR protocols (P = 0.96).
Correlations, The change in vastus lateralis CSA following
8 wk of RT was positively associated with pre-RT (= 0.10,
Fig, 64) and pos-RT vastus lateralis CSA (7° = 0.22, Fig. 6B)
and negatively associated with the 8-wk accumulated TTV
(7 = 0009, Fig, 6C, all P = 0405). In addition, the integrated
O-48-h MyoPS increase was positively associated with the
TTV of the 17th exercise session (= 0.10, Fig. 6D) and the
[Link] accumulated TTV (r? = 0.13, Fig. 6E, all P < 0.05),
DISCUSSION
This study is the first to compare the individual muscle
hypertrophic responses to 8 wk of standardized progressive RT
protocol with a protocol that systematically manipulated com-
mon RT variables in resistance-trained young men using a
within-subject design, We combined chronic measurements of
A 20, 7 B 3. :
Su Su
= é
g g
Ea 2
Fas Bos
CON VAR
Fig. § Igrated 0~
See MeT#00s fr details} and CON protect responses (8). Basa
001)
CON VAR-oad
rates of muscle myoibllar protein syntbesis(MyePS) in espoase to a acute bout of resiance exercise of the contol (CON) and
le (VAR) protocols) and he integrated O48 rates of MyoPS increase scparted by
‘means, and dots represent individual responses. *Signficanly dif
CON VARsets CON VARs CON VAR est
ch VAR condition (VAR- oad, VAR-sets, VARcece, VAR res
nt fom CON (P=
4 Appl Physi «di 0.1152j apple 003502019 + www japon MUSCLE PROTEIN SYNTHESIS AND HYPERTROPHY IN TRAINED MEN
‘Change in CSA (em!) >
si
B c
iB 6 20) P=00s
= 2 0.307
Zs a"
a = 0
& 2 &
i é*
4 I © ot
ar) 10000 20000 300000
CSA Pre (cm Swk TTY (kg)
MyoPS (day &
1000015000 20000 25000
17" session TTV (kg)
2200000
Sk TTY (ke)
“300000
Fig. 6 Comolatons hotweun dependent variables [change in CSA with CSA Pre (A), CSA Post (B) and Sovk TTY (C): and MyoPS with the 17's sesion TV
(Dy and 8-vk TTV (E)) CSA, vats lateralis cross-sectional area: MyoPS, myotibillar protein synthesis: Pre, baseline: Post afer 8 wk of resistance taining:
TTY, total taining volume
vastus lateralis CSA with acute measurements of daily imtegra-
tive MyoPS in a rested state and in response to a single bout of
resistance exercise that corresponded in characteristics with the
assigned RT program. Consistent with our hypothesis, we
demonstrated 2 comparable increase in vastus lateralis CSA
following RT in CON and VAR, despite greater TTV for VAR.
We found marginally greater integrated rates of MyoPS for
some VAR conditions compared with CON, Thus, both a
greater TTV and a slightly greater MyoPS response failed t0
elicit an additional muscie hypertrophic response for VAR
chronically compared with CON, We also report no “nonre-
sponders” in terms of RT-induced muscle hypertrophy. Intra-
subject analysis revealed a low variability in the change of
muscle CSA between legs, with no participants benefiting to a
‘greater extent from performing a specific RT protocol. Never-
theless, we observed a large between-subjects variability in the
muscle hypertrophic response for both CON and VAR proto-
cols. Taken together, these data suggest that an intrinsic indi-
vidual predisposition, rather than the extrinsic manipulation of
variables within an RT program, provides a stronger determi-
rant of subject-specific RT-induced muscle hypertrophy, at
least when RT protocols are performed with a high level of
effort in resistance-trained young men,
‘Training status is a key determinant of the muscle hyper-
trophic responses to RT (2, 16, 17, 42). To exclude the
possibility of a novel effect of RT on the muscle hypertro-
phic response (2), in the present study we recruited a cohort
Of resistance-trained young men. We report that the standard
progressive RT protocol (CON) and the protocol that sys-
ematically manipulated exercise load, volume, type of con-
traction, and interset rest interval (VAR) elicited similar
increases in vastus lateralis CSA following 8 wk of RT.
Thus, it seems unnecessary to often change RT composition
to avoid a plateau in the muscle hypertrophic response in
trained individuals, at least when RT is performed up to of
close to concentric failure (as were all the conditions used in
the present study). Consistent with this observation, we (8,
15, 30-33, 36) and others (3, 38, 40) have demonstrated
similar muscle hypertrophic responses between high-level
effort RT protocols when manipulating one single specific
RT variable at a time (.e., load, volume, type of contraction,
interset rest interval, intensity, or frequency). Other studies
with more complex manipulations of RT involving different
training schemes, e.g. bodybuilding- versus powerlifting-
focused RT programs (41), constant repetition versus varied
repetition RT routines (38), and crescent pyramid versus
ddrop-set RT systems (5), but still demanding high levels of
effort in each RT session, also reported no difference in the
muscle hypertrophic response between RT protocols, There-
fore. we expand the previous results, demonstrating that a
systematic, daily manipulation of common RT variables
also appears ineffective in potentiating the muscle hyper-
trophic response, at least when examined at the group level.
In contrast, it has been proposed that the training volume is,
an RT variable that could have an impact in the RT-induced
hypertrophic response (10, 39), We observed a positive asso-
ciation between the TTV of the 17th exercise session with the
(0-48-h integrated response of MyoPS to an acute bout of
resistance exercise. The TTV in the 17th session and the
(0-48: integrated MyoPS increase after the exercise bout were
seater for VAR than CON, and both results were primarily
driven by VAR-sets whereby the number of sets was increased
by 50%, We also observed a positive association between the
S-wk TTY and the MyoPS response to an acute exercise bout.
‘These observations could indicate a positive relation between
TTV and the integrated MyoPS response (0 an acute bout of
4 Appl Physi «di 0.1152j apple 003502019 + www japon 812
resistance exercise. Even so, the magnitude of variance in
MyoPS that could be explained by the variance in the 17th
session TTV and the 8-wk TTV was low (10% and ~13%,
respectively), indicating that TTV can modulate the muscle
anabolic response but to a lesser extent than is often purported,
atleast for high-effort RT protocols in trained individuals,
Both CON and VAR RT protocols increased MyoPS from
rest at 24 h and 48 h after exercise. Comparing between legs,
the MyoPS response was only marginally greater for VAR=
load (ie., post hoe test indicated that the value at 24 h was
‘greater for VAR-Ioad) and VAR-sets (ie., main group effect
and the integrated 0-48-h MyoPS response favoring VAR-
sets) compared with CON. In the VAR-load condition, the
number of repetitions was markedly increased because of
the low exercise load used, and in the VAR-sets condition, the
number of sets was inereased. These results are consistent with
a possible relationship between training volume and MyoPS
response. However, these marginal differences in the inte-
rated rates of MyoPS between protocols were not sufficient 10
result in a greater chronic hypertrophic outcome for VAR.
‘Thus, the magnitude of increase in 0—48-h integrated MyoPS.
ited by CON (-96% of the VAR MyoPS response on
average) was likely sufficient to maximize muscle hypertro-
phy, and further increases in MyoPS (~4%) were not reflective
of the chronic hypertrophic outcome. For what was used. this
“extra” non-hypertrophy-oriented MyoPS increase is) un-
known, We can speculate that a degree of muscle damage
requiring repair and remodeling could have influenced the
MyoPS results as we have shown before (18). Eccentric con-
tractions and/or high-volume protocols, as in some VAR con-
ditions used in the present study, are known to result in muscle
damage (27). However, in the’ present study, the degree of
muscle damage induced by eccentric muscle contractions was
likely low because we recruited previously resistance-trained
subjects, and the assessment of MyoPS was conducted only in
response to the final training session (13, 18, 22). Moreover,
the MyoPS response for VAR-eoe was similar 10 CON (see
Fig. 4C). Thus, if muscle damage did upregulate MyoPS in the
present study, the magnitude of this increase was minimal and
was likely related more to the higher TTV in some VAR
conditions than to eccentric muscle contractions. As such, we
speculate that a “training volume threshold” exists with regards
to stimulating MyoPS for muscle hypertrophy with a propor-
tion of the extra”) MyoPS response directed toward non-
hypertrophic outcomes, such as muscle repair and remodeling.
This hypothesis warrants further investigation. Consistent with
‘our MyoPS results, the 8-wk TTV completed during CON was
sutficient to facilitate a comparable level of muscle hypertro-
phy than VAR, despite a greater 8-wk TTV in VAR. Previous
studies also demonstrated similar muscle hypertrophic re-
sponses between protocols that resulted in different absolute
TTV (8, 23, 33). Aside from differences in absolute TTV
between protocols. in the present study it was evident that the
progression of TTV throughout RT followed a similar pattern
between CON and VAR, ie, no statistical differences between
slope progressions over the 8-wk RT period. Therefore, the
TTY progression could be an important variable to maximize
the muscle hypertrophic responses in resistance-trained men, at
least when determined at the group level. This speculation
should be addressed in future studies comparing different TTV
slopes progression. Nevertheless, the present study demon-
MUSCLE PROTEIN SYNTHESIS AND HYPERTROPHY IN TRAINED MEN
strates that systematic manipulations of RT variables through-
cout training sessions, which resulted in higher TTV and mar-
sinally greater acute MyoPS responses, are not necessary to
maximize RT-induced muscle hypertrophic responses. in
trained young men at a group level.
Our within-subjects unilateral study design enabled us to
determine the impact of manipulating RT variables in muscle
hypertrophic outcomes not only at a group level but also
pethaps more importantly on an individualized basis. Notably,
all individuals were considered “responders” in terms of mus
le hypertrophy when completing the CON protocol, and only
‘one participant was considered (marginally) to be a “nonte-
sponder” following the VAR protocol, reporting 2.4% in-
crease in CSA, whereas the cut point was 2.8%. Thus, in our
hands, all trained men demonstrated a significant muscle hy~
pertrophic response (0 at least one of the high-effort RT
protocols. performed, despite prior evidence of “nonre-
sponders” among trained men using a lower sample size and a
distinct RT program (24), Examining the effect in the muscle
hypertrophic responses intraindividual (ie., between legs) pro-
moted by CON and VAR, we revealed that no subjects bene-
fited to a greater extent from one specific RT protocol. In fact,
the average difference in MyoPS between protocols (i.e..
between legs, within subject) was only 0.08%, and the maxi-
mum difference was 0.21%. We also report similar low intra~
individual variability in the measurements of muscle CSA,
with an average difference between protocols of only 0.91%
and the maximum difference within 2 typical errors (not
significant) at 1.75%, These results contrast with our previous
study in which’ we manipulated only RT weekly frequency
(5). In that study, we demonstrated that ~32% of participants,
benefited more from training 5X per week (higher TTV), but
"7% of participants responded more favorably
to 2 or 3X per week (lower TTV) (15). Therefore, manipulat-
ing several RT variables throughout training versus the manip-
ulation of a single RT variable appears to result in distinct
intraindividual outcomes. Moreover, these observations indi
cate that a high TTV could impair the muscle hypertrophic
response in some individuals. Accordingly, in the present
study, we observed a negative relationship between the 8-wk
‘TTV and the change in vastus lateralis CSA after 8 wk of RT.
It is possible that for some participants the assigned RT
program could have resulted in a significant increase in TTV
compared with what they were accustomed to in their previous,
training regimen, This notion corroborates with the proposal
that avery high TTV may blunt the muscle hypertrophic
response in some individuals to some extent, a the Variance in
‘muscle CSA change that could be explained by the variance in
TTY was low (~95). Taken together with group results, these
analyses demonstrate that the individual responsiveness (0
muscle hypertrophy reported in the present study was not
‘modulated by the systematic manipulation of several common
RT variables throughout RT.
The between-subjects (i... within each protocol) variability
in the muscle hypertrophic response to RT was large. Our CV
analyses revealed a between-subjects variability of ~3.3% per
session in MyoPS for CON and VAR. which translated 10 a
high between-subjects variability (~38%) in the increase in
‘muscle CSA for both RT protocols. Therefore, the between
subjects variability was more than 40-fold greater than the
intrasubject variability (reported on the paragraph above) for
4 Appl Physi «di 0.1152j apple 003502019 + www japon MUSCLE PROTEIN SYNTHESIS AND HYPERTROPHY IN TRAINED MEN
both MyoPS and muscle CSA responses. These results show
that the influence of manipulating RT variables (variability
between legs, intrasubject) on MyoPS and muscle CSA is
substantially smaller than the effect of individual responsive
ness (variability betweer-subjects). Similarly, previous large-
scale studies reported wide ranges of RT-induced hypertrophic
changes from —1.8 to 9.2 kg of lean body mass in Ref. 14 and
from —11% to 30% change in muscle size in Ref. 4, irrespec-
tive of age or sex. We showed that ina sample of trained young
men, the individualized increase in vastus lateralis CSA ranged
from 2.9% to 13.7% in CON and from 2.4% to 13.5% in VAR,
equating to 108% and 11.1% points of the between-subjects
\ifferences, respectively. For both MyoPS responses and mus-
cle CSA changes, the Levene’s test showed similar between-
subjects variability between CON and VAR protocols. The
large but similar between-subjects variability between CON
and VAR supports the notion that the type of RT protocol
performed (CON or VAR) did not impact the high between-
individual variability in RT-induced muscle hypertrophy even
in trained subjects. Therefore, our data indicate that the intrin-
sic individual capacity to respond to RT is of greater impor-
tance than extrinsic training factors in determining. muse
hypertrophic outcomes. Corroborating with the above, we also
report that individual pre-RT vastus lateralis CSA values were
predictive (though account for only ~10%) of the change in
vastus lateralis CSA with RT. This association suggests that, t0
some extent, the magnitude of RT-induced muscle hypertrophy
is greater in previously larger muscles. Although this interpre
tation of results may be considered counterintuitive, itis
important to emphasize that our participants were previously
trained and therefore had already responded to previous train-
ing before embarking on the present study. As such, an indi-
vidual with larger muscles at the start of the study already
reflected a “good responder” to his previous training experi-
ence. Moreover, we also observed a positive association be
tween vastus lateralis CSA values post-8 wk of RT and the
RT-induced muscle hypertrophy, demonstrating that once a
00d “responder” (CSA pre-RT association with CSA change),
this individual will “keep responding” (CSA pos-RT associ
tion with CSA change), at least to 8-wk progressive RT.
‘Therefore. we propose that intrinsic individual factors are key
determinants and are the main source of variability of the
muscle hypertrophic responses compared with extrinsic RT
‘composition, atleast when high-level effort (resulting in mod
erate-to-high TTV) protocols are performed by trained sub-
ects.
‘Although there are many strengths of the present study,
including the within-subjects study design and the inclusion of
both acute metabolic (i.e, MyoPS) and chronic (vastus lateral
CSA) measurements, there are also limitations. First, we per-
formed the muscle biopsy and the ultrasound measurements
at single sites of the vastus lateralis. It is possible that the
VAR-ece, for example, induced a greater magnitude of muscle
hypertrophy distally in the muscle (20). Even so, when muscle
Volume was considered in that study (20), no benefit was
detected for eccentric RT compared with the concentric RT.
Second, besides intrinsic factor. itis also feasible that extrin-
sic factors such as the habitual diet (mainly the amount of
protein ingested) contributed to modulating the muscle hyper-
trophic response to RT (35), Although in the present study we
«id not control diet, we did administer 30 g of whey protein
813
after each RT session to stimulate a maximal MyoPS response
(43). Importantly, the impact of controlling dietary intake on
the muscle hypertrophic response might not be large in healthy
subjects, as a recent review indicated that self-reported dietary
habits, including energy intake and even protein consumption,
did not differ between distinct levels of responders to muscle
hypertrophy (37).
In summary, the present study reveals a similar muscle
hypertrophy response, both at the group and intrasubject levels,
10 systematically manipulating RT variables during an S-wk
program and a standard progressive RT in resistance-trained
‘young men, These observations were evident despite a higher
‘TTV and integrated MyoPS responses to acute exercise for
some VAR protocols than CON. Thus, it appears that any
modest further increase in MyoPS and higher training volumes
do not potentiate the chronic muscle hypertrophic response.
‘We reported no nonresponders to RT and a low intrasubject
variability but a wide range of muscle hypertrophic responses
between subjects, irrespective of RT protocol. Therefore, we
conclude that intrinsic individual factors are key determinants
fof the muscle hypertrophic responses in trained young men
‘compared with the extrinsic manipulation of the RT composi-
tion, at least when high-level effort protocols are performed.
ACKNOWLEDGMENTS
‘The autos sehnowledg ll he subjects who participate in this study nd
Supley Laboratérie de Alimentos e Splementos Notriionais (Max Titanium.
‘Sto Paulo, Bru) for donating whey protein,
GRANTS
“This work wa supporto by the So Plo Research Foundation (Grant nos.
2016242591 and 2018/13064-0 oF. Dams, Grant no. 2017I0S331-6 to V.
Angles, nd Grant no. 2017/04299-1 to C.A. Lard C. A. Libr also was
‘upporcd by the National Cone for Scientific and Technological Develop.
‘ment (Grant no, 30280120189),
D
LOSURES,
[No conflicts of interest, nancial or otherwise, are declared bythe authors.
AUTHOR CONTRIBUTIONS
ED, SMP. CU, and CAL. conceived an designs research; FD, V.A,
NS. SDS, LARC, MEL, and MSC, performed experiments FD. VA
and OCW. analyzed data: FD. VA, OCW. and CALL interpreted resus of
txpeiments FD. prpated figures, FD, OCW, apd CL. deed manuscripts
PD, VA. SMP. OCW, CU, NS. SDS. LARC, MEL, MSC, and
CALL eed and revi mans FD, V.A, SMP_OCW.CU-NS,SDS.
LARC, MEL, MSC. and CAL- appre find sexon of mascot
RI
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