Daily Myofibrillar Protein Synthesis Rates in Response to Low- and High-Frequency Resistance Exercise Training in Healthy, Young Men

in International Journal of Sport Nutrition and Exercise Metabolism
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  • 1 University of Birmingham
  • 2 Maastricht University Medical Centre
  • 3 Centre for Endocrinology, Diabetes and Metabolism
  • 4 NIHR Birmingham Biomedical Research Centre

The impact of resistance exercise frequency on muscle protein synthesis rates remains unknown. The aim of this study was to compare daily myofibrillar protein synthesis rates over a 7-day period of low-frequency (LF) versus high-frequency (HF) resistance exercise training. Nine young men (21 ± 2 years) completed a 7-day period of habitual physical activity (BASAL). This was followed by a 7-day exercise period of volume-matched, LF (10 × 10 repetitions at 70% one-repetition maximum, once per week) or HF (2 × 10 repetitions at ∼70% one-repetition maximum, five times per week) resistance exercise training. The participants had one leg randomly allocated to LF and the other to HF. Skeletal muscle biopsies and daily saliva samples were collected to determine myofibrillar protein synthesis rates using 2H2O, with intracellular signaling determined using Western blotting. The myofibrillar protein synthesis rates did not differ between the LF (1.46 ± 0.26%/day) and HF (1.48 ± 0.33%/day) conditions over the 7-day exercise training period (p > .05). There were no significant differences between the LF and HF conditions over the first 2 days (1.45 ± 0.41%/day vs. 1.25 ± 0.46%/day) or last 5 days (1.47 ± 0.30%/day vs. 1.50 ± 0.41%/day) of the exercise training period (p > .05). Daily myofibrillar protein synthesis rates were not different from BASAL at any time point during LF or HF (p > .05). The phosphorylation status and total protein content of selected proteins implicated in skeletal muscle ribosomal biogenesis were not different between conditions (p > .05). Under the conditions of the present study, resistance exercise training frequency did not modulate daily myofibrillar protein synthesis rates in young men.

The muscle hypertrophic response to resistance exercise training can be modulated by manipulating variables, such as absolute load, total exercise volume, proximity to failure, and rest interval between exercise sets (Burd et al., 2010b; Mitchell et al., 2012; Schoenfeld et al., 2016). Less clear is the impact of resistance exercise training frequency (i.e., the number of times a muscle group is exercised over a given period of time) on muscle hypertrophy. Understanding the relative importance of exercise training frequency is necessary to optimize the skeletal muscle adaptive response to prolonged resistance exercise training.

While some studies have shown muscle hypertrophy to be enhanced by a higher (i.e., two or more times per week) resistance exercise training frequency (Schoenfeld et al., 2015; Zaroni et al., 2018), most have shown no differences (Schoenfeld et al., 2018). However, most studies to date have examined the impact of resistance exercise training frequencies in the range of one to three times per week. It is possible that higher resistance exercise training frequencies (e.g., five times per week) are required to enhance muscle protein synthesis rates and subsequent muscle hypertrophy. The evidence currently available is equivocal, with one study (Zaroni et al., 2018) showing greater muscle hypertrophy with a relatively high- (five times per week) resistance exercise training frequency, whereas another study (Gomes et al., 2018) reported no differences. As such, the impact of high- versus low-resistance exercise training frequency on muscle hypertrophy remains unclear.

Muscle hypertrophy following prolonged resistance exercise training is the product of sustained elevations in muscle protein synthesis that exceed muscle protein breakdown. It has recently been posited that relatively high-resistance exercise training frequency is required to maximize muscle hypertrophy by regularly stimulating the acute myofibrillar protein synthetic response to a single bout of resistance exercise (Dankel et al., 2017). Following an acute bout of resistance exercise, myofibrillar protein synthesis rates remain elevated for approximately 24 hr before returning to basal levels (Burd et al., 2011; Damas et al., 2016). Furthermore, a relatively low volume (∼three sets) of resistance exercise appears to maximize postexercise myofibrillar protein synthesis rates, at least in young men (Burd et al., 2010a; Kumar et al., 2012). On this basis, it has been speculated that more frequent, low-volume, resistance exercise could induce more frequent elevations in myofibrillar protein synthesis rates, which in the long term, would lead to greater muscle hypertrophy (Dankel et al., 2017). While plausible, this hypothesis has yet to be tested.

The purpose of the present study was to compare daily myofibrillar protein synthesis rates, measured using deuterated water (2H2O) under free-living conditions, in young men over a 7-day period while performing low- (LF; once per week) versus high- (HF, five times per week) frequency resistance exercise training. As muscle protein synthesis rates are facilitated by transcriptional capacity (Figueiredo & McCarthy, 2019), we also aimed to assess whether resistance exercise training frequency impacts the phosphorylation status and total protein content of selected proteins implicated in ribosomal biogenesis.

Methods

Participants and Ethical Approval

Nine young men participated in the present study between February 2018 and August 2018. The participant characteristics are presented in Table 1. Prior to providing written consent, each volunteer was informed of the experimental procedures and potential risks. The participants were screened prior to inclusion and deemed healthy based on their responses to a general health questionnaire. The inclusion criteria included being male, being aged 18–35 years, having a body mass index between 18.5 and 29.99 kg/m2, being recreationally active and untrained (i.e., performing activities of daily living and recreation, but no regular lower body resistance exercise in the last year), and being willing and able to comply with all procedures. The exclusion criteria included having a lidocaine allergy, hypertension (≥140/90 mmHg) or bleeding disorders, current participation in another study, being a current/recent smoker, vegetarian/vegan, or a history of substance abuse, and/or taking prescription or nonprescription medication or supplements that may influence normal metabolic responses. The study was approved by the National Research Ethics Service Committee West Midlands, Edgbaston, United Kingdom (reference: 17/WM/0430) and conformed to standards for the use of human participants in research as outlined in the Declaration of Helsinki. The intervention was registered at clinicaltrials.gov prior to data collection (identifier: NCT03275779).

Table 1

Participants’ Characteristics at Baseline

VariableValue
Age (years)21.0 ± 2.3
Height (m)1.79 ± 0.07
Body mass (kg)72.4 ± 7.1
BMI (kg/m2)22.7 ± 2.6
LF leg press 1RM (kg)104 ± 22
HF leg press 1RM (kg)106 ± 22
LF leg extension 1RM (kg)82 ± 11
HF leg extension 1RM (kg)81 ± 12

Note. Values are mean ± SD. n = 9. BMI = body mass index; 1RM = one-repetition maximum; LF = low frequency; HF = high frequency.

Pretesting

During the initial screening visit, the participants underwent maximal strength testing and a familiarization session. First, the participants completed a 5-min warm-up of self-paced cycling. Maximal leg strength was then determined for each leg on a plate-loaded 45° leg press. This process was then repeated on a weight-stacked leg extension machine. The participants first performed a submaximal warm-up set of eight to 10 repetitions and had their lifting form critiqued and corrected when necessary. This was followed by sets at progressively increasingly loads, until only one valid repetition could be competed. The load for each set was chosen based on the participant’s rating of perceived exertion following the previous set. A 3-min rest interval was provided between each set. Once completed, the corresponding load (∼70% one-repetition maximum [1RM]) to be used during the subsequent familiarization session and resistance exercise sessions was calculated.

To familiarize the participants with the exercise volume to be completed during the experimental trials and to minimize muscle damage associated with an unfamiliar bout of resistance exercise (Damas et al., 2016; Nosaka et al., 2001), the participants completed five sets of bilateral leg press, followed by five sets of bilateral leg extension at ∼70% 1RM, with a 2-min rest between each set. The total exercise volume completed during the familiarization (12,121 ± 2,206 kg) was similar to that completed in total by both legs during the experimental resistance exercise sessions (11,952 ± 2,700 kg). Pretesting and the first experimental trial (Day 0) were separated by ≥7 days.

Study Overview

A study overview is presented in Figure 1. The study was designed to assess whether resistance exercise frequency impacts daily myofibrillar protein synthesis rates measured under free-living conditions. The participants arrived at ∼08:00 a.m. in a fasted state on Day 0 and had a muscle biopsy collected. All muscle biopsies were collected from the vastus lateralis using the Bergström needle with manual suction, under local anesthesia (1% lidocaine). The participants then completed a 7-day basal period (BASAL), where they were instructed to maintain habitual physical activity (i.e., activities of daily living and recreation without structured physical activity). The participants returned on Day 7 and had a second muscle biopsy collected from the alternate leg. Following this, the participants had each leg randomly allocated to either the LF or HF resistance exercise (see “Resistance exercise sessions” section below). A bout of LF and HF was completed on Day 7. Approximately 48 hr later (Day 9), the participants returned and had one muscle biopsy collected from each leg. This was followed by the second bout of HF. Additional bouts of HF were completed on Days 10, 11, and 12. The participants returned on Day 14 (∼48 hr after the final HF bout) and had the final muscle biopsies collected from each leg, signifying the end of the study. A pedometer was worn throughout, and weighed food diaries were completed to assess the daily step count and dietary intake, respectively, across the study.

Figure 1
Figure 1

—Study overview. LF = low frequency; HF = high frequency; BASAL = 7-day period of habitual physical activity.

Citation: International Journal of Sport Nutrition and Exercise Metabolism 31, 3; 10.1123/ijsnem.2020-0274

2H2O Dosing Protocol

The 2H2O dosing protocol consisted of 1 dosing day and 16 maintenance days (Shad et al., 2019). The 2H2O protocol was well tolerated, with none of the participants reporting any adverse effects.

Dietary Intake and Physical Activity

On the evening prior to each experimental visit involving muscle biopsies, the participants received the same standardized meal (∼689 kcal, providing ∼55 energy% [En%] carbohydrate, ∼20 En% protein, and ∼25 En% fat). A weighed 4-day food diary was completed over the first 7-day period of habitual physical activity (BASAL) and over the second 7-day period of LF and HF resistance exercise to assess energy and macronutrient intake. The participants were required to include 2 weekdays and both weekend days in their recordings. The dietary records were analyzed using Dietplan software (version 6.70.67; Forestfield Software Ltd., Horsham, United Kingdom). The participants were instructed to refrain from structured physical activity throughout the study, other than the prescribed resistance exercise completed as part of the study. The participants were also provided with a hip-worn pedometer (Yamax Digi-Walker SW-200; Yamax, Bridgnorth, United Kingdom) to wear throughout the study to assess the daily step count.

Resistance Exercise Sessions

Using a within-subject design, the participants had one leg randomized to complete LF and the other to complete HF. Prior to all resistance exercise sessions, the participants completed a 5-min warm-up of self-paced cycling at ∼100 W. On Day 7, a single bout of unilateral high-volume LF was completed. This consisted of five sets of 10 repetitions at ∼70% 1RM on the 45° leg press machine, followed by five sets of 10 repetitions at ∼70% 1RM on the weight-stacked leg extension machine. A single bout of unilateral low-volume HF was also completed on Day 7, using the opposite leg. This consisted of one set of 10 repetitions at ∼70% 1RM on the 45° leg press machine, followed by one set of 10 repetitions at ∼70% 1RM on the weight-stacked leg extension machine. A further four bouts of unilateral low-volume HF was completed on Days 9, 10, 11, and 12. This design ensured that total exercise volume and the number of sets completed were matched between the LF and HF conditions. The total exercise volume was intentionally matched, as exercise volume has been shown, at least when comparing low volumes of resistance exercise, to modulate the magnitude of the myofibrillar protein synthetic response to resistance exercise (Burd et al., 2010a). Two minutes of rest was allowed between all sets, and 5 min of rest was allowed between the bouts of LF and HF on Day 7. Following all resistance exercise sessions, the participants ingested 25 g of whey protein powder (Impact Whey Protein; Myprotein, Cheshire, United Kingdom), containing 21 g of protein (equating to ∼0.29 g/kg), dissolved in water.

Body Water 2H Enrichment

Body water 2H enrichment was analyzed from daily saliva samples collected throughout the study, as previously described (Holwerda et al., 2018; Shad et al., 2019).

Myofibrillar-Bound 2H-Alanine Enrichment

2H-alanine enrichment in the myofibrillar fraction of muscle biopsy samples was measured, as previously described (Shad et al., 2019).

Western Blotting

Western blot analyses were performed on the sarcoplasmic fraction obtained during myofibrillar protein extraction, as previously described (McKendry et al., 2019). The following primary antibodies were used ([1:1000] in 2.5% bovine serum albumin): total eukaryotic translation initiation factor 4E (eIF4E) (ab33766), phospho-eIF4E Ser209 (ab76256), total cyclin D1 (ab16663), and total upstream binding factor (ab244287), all purchased from Abcam (Abcam, Cambridge, United Kingdom). Imaging was undertaken using a G:Box Chemi-XR5 (Syngene, Cambridge, United Kingdom), and bands were quantified using Image Studio Lite (LI-COR Biosciences, Lincoln, NE).

Calculations

Myofibrillar protein fractional synthetic rate (FSR) was determined using the incorporation of 2H-alanine into myofibrillar protein and the mean 2H enrichment in body water between sequential biopsies, corrected by a factor of 3.7, as the surrogate precursor based upon 2H labeling during de novo alanine synthesis (Belloto et al., 2007). The standard precursor–product method was used to calculate FSR:

FSR (%/day)=(Em2Em1Eprecursor×t)×100,
where Em1 and Em2 are the myofibrillar protein-bound 2H-alanine enrichments between sequential muscle biopsies. Eprecursor represents the mean body water 2H enrichment between sequential biopsies, corrected by a factor of 3.7, based upon the 2H labeling of alanine during de novo synthesis (Belloto et al., 2007). t represents the time between sequential biopsies in days.

Statistics

Based on the hypothesis that HF resistance exercise training would result in more frequent elevations in myofibrillar protein synthesis rates compared with low-frequency (LF) resistance exercise training, and previous research (Holwerda et al., 2018; Wilkinson et al., 2014), an effect size of 1.1 was estimated. Sample size calculations showed that n = 9 would be sufficient to detect a difference in daily myofibrillar protein synthesis rates between the LF and HF conditions over the 7-day exercise training period, using a two-tailed paired samples t test (80% power, α level of .05, G*Power, Heinrich Heine University Düsseldorf, Düsseldorf, Germany). All statistical analyses were performed using SPSS (version 25.0; IBM Corp., Armonk, NY). The differences between the 7-day basal period and the 7-day exercise period (i.e., BASAL vs. LF/HF) for daily step count and dietary intake were compared using paired sample t tests. The differences between exercise conditions (LF vs. HF) for exercise variables (i.e., maximal strength and total exercise volume) were compared using a paired sample t test. Body water 2H enrichment was analyzed using a one-factor repeated-measures analysis of variance, with time as the within-subjects factor. Myofibrillar protein FSR over the 7-day resistance exercise training period was compared between LF and HF conditions using a paired samples t test (n = 9). All other comparisons over time and between conditions for myofibrillar protein FSR were analyzed using two-factor repeated-measures analysis of variances (Condition × Time), with condition (BASAL vs. LF vs. HF) and time (Days 0–7, 7–9, 9–14, and 7–14) as subject factors. Intracellular signaling was analyzed using a two-factor repeated-measures analysis of variance (Condition × Time), with condition (BASAL vs. LF vs. HF) and time (Days 7, 9, and 14) as within-subject factors. A biopsy sample for one participant could not be collected on Day 9, and thus, the myofibrillar protein FSR data for Days 7–9 and 9–14 and all intracellular signaling data were analyzed on n = 8. When a significant main effect or interaction was found, t tests with Bonferroni correction for multiple comparisons were performed. All data are presented as mean ± SD.

Results

Exercise Variables

The maximal strength values at the baseline were not different between the LF and HF conditions for the leg press (p = .397) and leg extension (p = .650) exercises (Table 1). By design, the total exercise volume completed was not different between the LF (5,933 ± 1,357 kg) and HF (6,019 ± 1,347 kg) conditions (p = .121).

Daily Step Count and Dietary Intake

The daily step count and dietary intake are presented in Table 2. The daily step count was not different between BASAL and the 7-day period of resistance exercise (p = .167). The relative contribution of dietary fat to overall energy intake significantly decreased during the period of resistance exercise (p = .041). There was also a trend for daily protein intake (p = .061) and protein intake relative to body weight (p = .089) to increase during the period of resistance exercise. All other dietary variables were unchanged across the study.

Table 2

Daily Step Count and Dietary Intake During the 7-Day Period of Habitual Physical Activity (BASAL) and 7-Day Period of LF and HF Resistance Exercise

VariableBASALLF/HFp value
Daily step count10,000 ± 2,42011,458 ± 1,871.167
Energy intake (kcal/day)2,253 ± 3162,336 ± 208.477
Protein (g·kg−1·day−1)1.3 ± 0.41.5 ± 0.2.089
Protein intake (g/day)93 ± 25104 ± 15.061
Carbohydrate intake (g/day)278 ± 53280 ± 43.931
Fat intake (g/day)82 ± 1282 ± 8.906
Protein (En%)16 ± 518 ± 2.402
Carbohydrate (En%)51 ± 752 ± 4.602
Fat (En%)32 ± 330 ± 4*.041

Note. Values are mean ± SD. n = 9. En% = energy%; LF = low frequency; HF = high frequency.

*Significant difference between BASAL and LF/HF conditions (p < .05).

Body Water 2H Enrichment

Figure 2a presents the mean body water 2H enrichment. Following the loading phase on Day 2 and a single maintenance day on Day 1, body water 2H enrichment reached 0.55 ± 0.05% (Day 0). Body water 2H enrichment did not change significantly over the duration of the study, with an average body water 2H enrichment of 0.58 ±0.08% during BASAL and 0.62 ± 0.13% during the period of resistance exercise (p = .107).

Figure 2
Figure 2

—Body water 2H enrichment and daily myofibrillar protein FSR during a 7-day period of habitual physical activity (BASAL) and a 7-day period of LF and HF resistance exercise (n = 9). Data are displayed as mean ± SD with participants’ individual FSR. FSR = fractional synthesis rates; LF = low frequency; HF = high frequency.

Citation: International Journal of Sport Nutrition and Exercise Metabolism 31, 3; 10.1123/ijsnem.2020-0274

Myofibrillar Protein Synthesis

Daily myofibrillar protein synthesis rates were not different between the LF (1.46 ± 0.26%/day) and HF (1.48 ± 0.33%/day) conditions over the entire 7-day exercise period (Figure 2b; p = .801). Moreover, there were no significant differences between the LF and HF conditions over the first 2 days (Days 7–9; 1.45 ± 0.41%/day vs. 1.25 ± 0.46%/day; p = .342; Figure 3) or over the last 5 days (Days 9–14) of the exercise period (1.47 ± 0.30%/day vs. 1.50 ± 0.41%/day; p = .342; Figure 3). The daily myofibrillar protein synthesis rates were not different from BASAL at any time point during LF or HF (p = .591; Figures 2b and 3).

Figure 3
Figure 3

—Daily myofibrillar protein FSR during a 7-day period of habitual physical activity (BASAL) and a 7-day period of LF and HF resistance exercise (n = 8). Data are displayed as mean ± SD with participants’ individual FSR. FSR = fractional synthesis rates; LF = low frequency; HF = high frequency.

Citation: International Journal of Sport Nutrition and Exercise Metabolism 31, 3; 10.1123/ijsnem.2020-0274

Intracellular Signaling

A main effect of time was observed for the eIF4E total protein content (p = .029; Figure 4a). Following correction for multiple comparisons, pairwise comparisons showed a tendency (p = .056) for greater total protein content 48 hr (i.e., Day 9) following the initial LF and HF resistance exercise bouts compared with Day 7. A main effect of time was also observed for the cyclin D1 total protein content (p = .046; Figure 4c). However, following correction for multiple comparisons, pairwise comparisons showed no significant difference between time points. There were no significant changes over time (p = .407) or differences between the LF and HF conditions (p = .345) for phosphorylation of eIF4E at Ser209 (Figure 4b). There were no significant changes over time (p = .217) or differences between the LF and HF conditions (p = .891) for upstream binding factor total protein content (Figure 4d).

Figure 4
Figure 4

—Impact of LF and HF resistance exercise on (a) total protein content of eIF4E, (b) phosphorylation of eIF4E at Ser209, (c) total protein content of cyclin D1, and (d) total protein content of UBF (n = 8). Data are mean ± SD. LF = low frequency; HF = high frequency; eIF4E = eukaryotic translation initiation factor 4E; UBF = upstream binding factor; BASAL/B = 7-day period of habitual physical activity.

Citation: International Journal of Sport Nutrition and Exercise Metabolism 31, 3; 10.1123/ijsnem.2020-0274

Discussion

The present study is the first to determine the impact that resistance exercise training frequency may have on myofibrillar protein synthesis rates. The major finding was that daily myofibrillar protein synthesis rates did not differ between volume-matched low and high frequency resistance exercise training performed over a 7-day period in young men. In line with these findings, resistance exercise training frequency did not modulate the phosphorylation status and total protein content of selected proteins implicated in skeletal muscle ribosomal biogenesis.

Manipulation of resistance exercise training frequency (i.e., the number of times a muscle group is exercised over a given period of time) has been proposed as a key factor determining exercise-training-induced muscle hypertrophy (Dankel et al., 2017; Schoenfeld et al., 2018). This is based on the premise that high-resistance exercise training frequency induces greater overall myofibrillar protein synthesis rates and thus results in a greater amount of time spent in a greater net positive protein balance (Dankel et al., 2017). In the present study, a unilateral exercise model was utilized whereby each participant had one leg assigned to complete resistance exercise training once per week (i.e., LF) and the other leg to complete resistance exercise training five times per week (i.e., HF). This experimental design ensured that factors known to influence day-to-day muscle protein synthesis rates (e.g., sleep [Saner et al., 2020], protein intake [Witard et al., 2014], dietary composition [van Vliet et al., 2017], and habitual physical activity [Shad et al., 2019]) were identical between conditions, thereby allowing the impact of different resistance exercise training frequency on myofibrillar protein synthesis rates to be assessed in isolation. In contrast to the aforementioned hypothesis, the findings of the present study demonstrate that, under volume-matched conditions, a high-resistance exercise training frequency did not result in greater daily myofibrillar protein synthesis rates. These findings lend support to the preponderance of evidence showing that resistance exercise training frequency has little impact on muscle hypertrophy (Barcelos et al., 2018; Schoenfeld et al., 2018).

The present data are in line with evidence showing no differences in muscle hypertrophy with a resistance exercise frequency of one versus five times per week (Gomes et al., 2018), but are inconsistent with findings showing greater muscle hypertrophy under similar conditions (Zaroni et al., 2018). It is important to note that the total exercise volume completed in the study by Zaroni et al. (2018) was significantly higher in the group with a resistance exercise training frequency of five times per week. In contrast, in the present study, the total exercise volume was intentionally matched between the LF and HF exercise training conditions, which likely explains the lack of agreement between the findings. Indeed, a recent meta-analysis, published while the present study was being undertaken, suggests that resistance exercise training frequency does not significantly impact muscle hypertrophy when conducted under volume-matched conditions (Schoenfeld et al., 2018). Taken together, it would appear that resistance exercise training frequency per se (i.e., under volume-matched conditions) does not impact daily myofibrillar protein synthesis rates or subsequent muscle hypertrophy in young individuals.

In contrast to most (Brook et al., 2016; Damas et al., 2016; Wilkinson et al., 2014), although not all (Davies et al., 2020), previous studies, resistance exercise training failed to induce a detectable increase in daily myofibrillar protein synthesis rates (Figure 3). The volume of resistance exercise completed in the high-volume, LF exercise bout would have been expected to increase daily myofibrillar protein synthesis rates, given that resistance exercise of a similar volume and relative intensity has previously been shown to increase muscle protein synthesis rates in young men (Wilkinson et al., 2014). As such, there appears to be no obvious explanation for the absence of a measurable increase in daily myofibrillar protein synthesis rates following resistance exercise training. A possible explanation is that the impact of resistance exercise training on myofibrillar protein synthesis was “diluted” over the measurement period, as 2H2O measures myofibrillar protein synthesis rates continuously, capturing all free-living activities, including diet, sleep, and inactivity. While more representative of long-term muscle hypertrophy and remodeling (Damas et al., 2016), the free-living nature of the 2H2O measurement may have masked the well-established increase in myofibrillar protein synthesis in the hours following resistance exercise (Burd et al., 2010a; Kumar et al., 2012).

An alternative explanation could be related to familiarizing the participants with resistance exercise prior to the study. During the screening visit, the participants completed a high-volume familiarization bout. Given that Damas et al. (2016) demonstrated that the 48-hr myofibrillar protein synthetic response following resistance exercise is no longer different from the resting values once the participants have been familiarized with resistance exercise, this may explain the undetectable increase in daily myofibrillar protein synthesis rates in the present study. A final possibility is that factors known to influence muscle protein synthesis rates (e.g., sleep [Saner et al., 2020] and energy balance [Areta et al., 2014]) could have differed during the basal period and the exercise period and thus could, in part, explain the lack of an exercise effect. It must be acknowledged that the inability to detect an increase in daily myofibrillar protein synthesis rates in response to resistance exercise training may also have precluded differences from being detected between LF and HF resistance exercise training.

As muscle protein synthesis is partly regulated by translational capacity (i.e., ribosomal biogenesis; Figueiredo & McCarthy, 2019), a secondary aim was to assess whether resistance exercise training frequency impacts the phosphorylation status and total protein content of selected proteins implicated in skeletal muscle ribosomal biogenesis (Figure 4). Transcription of ribosomal DNA requires the activation of eIF4E and cyclin D1, which can subsequently activate a number of transcription factors, including the upstream binding factor, which forms part of the preinitiation complex (Figueiredo & McCarthy, 2019). In line with previous findings (Figueiredo et al., 2016), there was a tendency (p = .056) for the total eIF4E protein content (Figure 4a) to increase 48 hr following the initial bouts of LF and HF resistance exercise training. Consistent with the finding that resistance exercise training frequency had no impact on daily myofibrillar protein synthesis rates, no differences were observed at any time point for any marker of skeletal ribosomal biogenesis between the LF and HF resistance exercise training (Figure 4). However, it should be acknowledged that skeletal muscle ribosomal biogenesis is activated at multiple time points following resistance exercise (Figueiredo et al., 2016), and thus, it is possible that biopsy timing, primarily intended to assess myofibrillar protein synthesis rates, missed differences that may have occurred at earlier time points.

Although total exercise volume was intentionally matched to isolate the impact of resistance exercise training frequency per se on daily myofibrillar protein synthesis rates, it should be considered that higher resistance exercise training frequencies can be used effectively to increase overall exercise volume for a given muscle group (Barcelos et al., 2018). Indeed, under nonvolume equated conditions, higher resistance exercise training frequencies have been associated with greater gains in muscle mass (Schoenfeld et al., 2018) and strength (Grgic et al., 2018). From a practical standpoint, high-resistance exercise training frequency may be considered a useful means of achieving a given exercise training volume, particularly when time is a limiting factor.

It is also important to note that any change in muscle mass is ultimately determined by the overall protein balance between the muscle protein synthesis and breakdown. While the absence of a measure of muscle protein breakdown may be considered a limitation of the present investigation, the myofibrillar protein synthesis measurements made in the present study align well with the general finding that volume-matched resistance exercise training frequency has no impact on muscle hypertrophy (Schoenfeld et al., 2018). Finally, this study was conducted in individuals unaccustomed to regular lower limb resistance exercise, but it is possible that higher resistance exercise frequencies could be of greater benefit to more resistance-trained individuals, as has been suggested previously (Dankel et al., 2017).

In conclusion, under the conditions of the present study, resistance exercise training frequency does not modulate daily myofibrillar protein synthesis rates or the phosphorylation status and total protein content of selected proteins implicated in skeletal muscle ribosomal biogenesis in young men. These findings suggest that, for a given exercise volume, resistance exercise training frequency has little impact on skeletal muscle hypertrophy.

Acknowledgments

The authors would like to acknowledge Joy Goessens and Annemie Gijsen (both from Maastricht University, The Netherlands) for their technical assistance with muscle sample analysis. The authors thank the study volunteers for their willingness to take part in the study. B.J. Shad, J.L. Thompson, A.M. Holwerda, L.J.C. van Loon, and G.A. Wallis assisted in the conception and design of research; B.J. Shad, J. Mckendry, Y.S. Elhassan, L. Breen, and G.A. Wallis performed experiments; B.J. Shad, J. Mckendry, and A.M. Holwerda analyzed samples; B.J. Shad and G.A. Wallis prepared figures and drafted the manuscript; B.J. Shad, J.L. Thompson, J. Mckendry, A.M. Holwerda, Y.S. Elhassan, L. Breen, L.J.C. van Loon, and G.A. Wallis edited and revised the manuscript; B.J. Shad, J.L. Thompson, J. Mckendry, A.M. Holwerda, Y.S. Elhassan, L. Breen, L.J.C. van Loon, and G.A. Wallis approved the final version of the manuscript. B.J. Shad and J. Mckendry were funded by the University of Birmingham “Exercise as Medicine” PhD studentships. None of the authors have any conflicts of interest or financial disclosures to declare.

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  • Belloto, E., Diraison, F., Basset, A., Allain, G., Abdallah, P., & Beylot, M. (2007). Determination of protein replacement rates by deuterated water: Validation of underlying assumptions. American Journal of Physiology—Endocrinology and Metabolism, 292(5), E1340E1347. PubMed ID: 17227960 doi:10.1152/ajpendo.00488.2006

    • Crossref
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    • Export Citation
  • Brook, M.S., Wilkinson, D.J., Mitchell, W.K., Lund, J.N., Phillips, B.E., Szewczyk, N.J., … Atherton, P.J. (2016). Synchronous deficits in cumulative muscle protein synthesis and ribosomal biogenesis underlie age-related anabolic resistance to exercise in humans. The Journal of Physiology, 594(24), 73997417. PubMed ID: 27654940 doi:10.1113/JP272857

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burd, N.A., Holwerda, A.M., Selby, K.C., West, D.W., Staples, A.W., Cain, N.E., … Phillips, S.M. (2010a). Resistance exercise volume affects myofibrillar protein synthesis and anabolic signalling molecule phosphorylation in young men. The Journal of Physiology, 588(16), 31193130. PubMed ID: 20581041 doi:10.1113/jphysiol.2010.192856

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burd, N.A., West, D.W., Moore, D.R., Atherton, P.J., Staples, A.W., Prior, T., … Phillips, S.M. (2011). Enhanced amino acid sensitivity of myofibrillar protein synthesis persists for up to 24 h after resistance exercise in young men. Journal of Nutrition, 141(4), 568573. PubMed ID: 21289204 doi:10.3945/jn.110.135038

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burd, N.A., West, D.W., Staples, A.W., Atherton, P.J., Baker, J.M., Moore, D.R., … Phillips, S.M. (2010b). Low-load high volume resistance exercise stimulates muscle protein synthesis more than high-load low volume resistance exercise in young men. PLoS One, 5(8), e12033. PubMed ID: 20711498 doi:10.1371/journal.pone.0012033

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    • Search Google Scholar
    • Export Citation
  • Damas, F., Phillips, S.M., Libardi, C.A., Vechin, F.C., Lixandrao, M.E., Jannig, P.R., … Ugrinowitsch, C. (2016). Resistance training-induced changes in integrated myofibrillar protein synthesis are related to hypertrophy only after attenuation of muscle damage. The Journal of Physiology, 594(18), 52095222. PubMed ID: 27219125 doi:10.1113/JP272472

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    • Search Google Scholar
    • Export Citation
  • Dankel, S.J., Mattocks, K.T., Jessee, M.B., Buckner, S.L., Mouser, J.G., Counts, B.R., … Loenneke, J.P. (2017). Frequency: The overlooked resistance training variable for inducing muscle hypertrophy? Sports Medicine, 47(5), 799805. PubMed ID: 27752983 doi:10.1007/s40279-016-0640-8

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Davies, R.W., Bass, J.J., Carson, B.P., Norton, C., Kozior, M., Wilkinson, D.J., … Jakeman, P.M. (2020). The effect of whey protein supplementation on myofibrillar protein synthesis and performance recovery in resistance-trained men. Nutrients, 12(3), 845. PubMed ID: 32245197 doi:10.3390/nu12030845

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Figueiredo, V.C., & McCarthy, J.J. (2019). Regulation of ribosome biogenesis in skeletal muscle hypertrophy. Physiology, 34(1), 3042. PubMed ID: 30540235 doi:10.1152/physiol.00034.2018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Figueiredo, V.C., Roberts, L.A., Markworth, J.F., Barnett, M.P., Coombes, J.S., Raastad, T., … Cameron-Smith, D. (2016). Impact of resistance exercise on ribosome biogenesis is acutely regulated by post-exercise recovery strategies. Physiological Reports, 4(2), e12670. PubMed ID: 26818586 doi:10.14814/phy2.12670

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Gomes, G.K., Franco, C.M., Nunes, P.R.P., & Orsatti, F.L. (2018). High-frequency resistance training is not more effective than low-frequency resistance training in increasing muscle mass and strength in well-trained men. The Journal of Strength and Conditioning Research, 33(Suppl 1), S130S139. PubMed ID: 29489727 doi:10.1519/jsc.0000000000002559

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    • Search Google Scholar
    • Export Citation
  • Grgic, J., Schoenfeld, B.J., Davies, T.B., Lazinica, B., Krieger, J.W., & Pedisic, Z. (2018). Effect of resistance training frequency on gains in muscular strength: A systematic review and meta-analysis. Sports Medicine, 48(5), 12071220. PubMed ID: 29470825 doi:10.1007/s40279-018-0872-x

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    • Search Google Scholar
    • Export Citation
  • Holwerda, A.M., Paulussen, K.J.M., Overkamp, M., Smeets, J.S.J., Gijsen, A.P., Goessens, J.P.B., … van Loon, L.J.C. (2018). Daily resistance-type exercise stimulates overall muscle protein synthesis rates in vivo in young males. Journal of Applied Physiology, 124(1), 6675. PubMed ID: 28935828 doi:10.1152/japplphysiol.00610.2017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kumar, V., Atherton, P.J., Selby, A., Rankin, D., Williams, J., Smith, K., … Rennie, M.J. (2012). Muscle protein synthetic responses to exercise: Effects of age, volume, and intensity. Journals of Gerontology Series A—Biological Sciences & Medical Sciences, 67(11), 11701177. PubMed ID: 22859389 doi:10.1093/gerona/gls141

    • Crossref
    • Search Google Scholar
    • Export Citation
  • McKendry, J., Shad, B.J., Smeuninx, B., Oikawa, S.Y., Wallis, G., Greig, C., … Breen, L. (2019). Comparable rates of integrated myofibrillar protein synthesis between endurance-trained master athletes and untrained older individuals. Frontiers in Physiology, 10, 1084. PubMed ID: 31543824 doi:10.3389/fphys.2019.01084

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mitchell, C.J., Churchward-Venne, T.A., West, D.W., Burd, N.A., Breen, L., Baker, S.K., & Phillips, S.M. (2012). Resistance exercise load does not determine training-mediated hypertrophic gains in young men. Journal of Applied Physiology, 113(1), 7177. PubMed ID: 22518835 doi:10.1152/japplphysiol.00307.2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nosaka, K., Sakamoto, K., Newton, M., & Sacco, P. (2001). The repeated bout effect of reduced-load eccentric exercise on elbow flexor muscle damage. European Journal of Applied Physiology, 85(1–2), 3440. PubMed ID: 11513318 doi:10.1007/s004210100430

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Saner, N.J., Lee, M.J.C., Pitchford, N.W., Kuang, J., Roach, G.D., Garnham, A., … Bartlett, J.D. (2020). The effect of sleep restriction, with or without high-intensity interval exercise, on myofibrillar protein synthesis in healthy young men. The Journal of Physiology, 598(8), 15231536. PubMed ID: 32078168 doi:10.1113/JP278828

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Schoenfeld, B.J., Grgic, J., & Krieger, J. (2018). How many times per week should a muscle be trained to maximize muscle hypertrophy? A systematic review and meta-analysis of studies examining the effects of resistance training frequency. Journal of Sports Sciences, 37(11), 12861295. PubMed ID: 30558493 doi:10.1080/02640414.2018.1555906

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Schoenfeld, B.J., Pope, Z.K., Benik, F.M., Hester, G.M., Sellers, J., Nooner, J.L., … Krieger, J.W. (2016). Longer interset rest periods enhance muscle strength and hypertrophy in resistance-trained men. The Journal of Strength and Conditioning Research, 30(7), 18051812. PubMed ID: 26605807 doi:10.1519/JSC.0000000000001272

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Schoenfeld, B.J., Ratamess, N.A., Peterson, M.D., Contreras, B., & Tiryaki-Sonmez, G. (2015). Influence of resistance training frequency on muscular adaptations in well-trained men. The Journal of Strength and Conditioning Research, 29(7), 18211829. PubMed ID: 25932981 doi:10.1519/JSC.0000000000000970

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Shad, B.J., Thompson, J.L., Holwerda, A.M., Stocks, B., Elhassan, Y.S., Philp, A., … Wallis, G.A. (2019). One week of step reduction lowers myofibrillar protein synthesis rates in young men. Medicine & Science in Sports & Exercise, 51(10), 21252134. PubMed ID: 31083048 doi:10.1249/mss.0000000000002034

    • Crossref
    • Search Google Scholar
    • Export Citation
  • van Vliet, S., Shy, E.L., Abou Sawan, S., Beals, J.W., West, D.W., Skinner, S.K., … Burd, N.A. (2017). Consumption of whole eggs promotes greater stimulation of postexercise muscle protein synthesis than consumption of isonitrogenous amounts of egg whites in young men. The American Journal of Clinical Nutrition, 106(6), 14011412. PubMed ID: 28978542 doi:10.3945/ajcn.117.159855

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wilkinson, D.J., Franchi, M.V., Brook, M.S., Narici, M.V., Williams, J.P., Mitchell, W.K., … Smith, K. (2014). A validation of the application of D2O stable isotope tracer techniques for monitoring day-to-day changes in muscle protein subfraction synthesis in humans. American Journal of Physiology–Endocrinology and Metabolism, 306(5), E571E579. PubMed ID: 24381002 doi:10.1152/ajpendo.00650.2013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Witard, O.C., Jackman, S.R., Breen, L., Smith, K., Selby, A., & Tipton, K.D. (2014). Myofibrillar muscle protein synthesis rates subsequent to a meal in response to increasing doses of whey protein at rest and after resistance exercise. The American Journal of Clinical Nutrition, 99(1), 8695. PubMed ID: 24257722 doi:10.3945/ajcn.112.055517

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    • Search Google Scholar
    • Export Citation
  • Zaroni, R.S., Brigatto, F.A., Schoenfeld, B.J., Braz, T.V., Benvenutti, J.C., Germano, M.D., … Lopes, C.R. (2019). High resistance-training frequency enhances muscle thickness in resistance-trained men. The Journal of Strength & Conditioning Research, 33(Suppl. 1), S140S151. PubMed ID: 31260419 doi:10.1519/jsc.0000000000002643

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Shad, Thompson, Mckendry, Breen, and Wallis are with the School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, United Kingdom. Holwerda and van Loon are with the Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands. Elhassan is with the Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom; and the Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, United Kingdom. Breen is also with the NIHR Birmingham Biomedical Research Centre, Birmingham, United Kingdom; and the MRC—Versus Arthritis Research UK Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, United Kingdom.

Wallis (g.a.wallis@bham.ac.uk) is corresponding author.
  • View in gallery

    —Study overview. LF = low frequency; HF = high frequency; BASAL = 7-day period of habitual physical activity.

  • View in gallery

    —Body water 2H enrichment and daily myofibrillar protein FSR during a 7-day period of habitual physical activity (BASAL) and a 7-day period of LF and HF resistance exercise (n = 9). Data are displayed as mean ± SD with participants’ individual FSR. FSR = fractional synthesis rates; LF = low frequency; HF = high frequency.

  • View in gallery

    —Daily myofibrillar protein FSR during a 7-day period of habitual physical activity (BASAL) and a 7-day period of LF and HF resistance exercise (n = 8). Data are displayed as mean ± SD with participants’ individual FSR. FSR = fractional synthesis rates; LF = low frequency; HF = high frequency.

  • View in gallery

    —Impact of LF and HF resistance exercise on (a) total protein content of eIF4E, (b) phosphorylation of eIF4E at Ser209, (c) total protein content of cyclin D1, and (d) total protein content of UBF (n = 8). Data are mean ± SD. LF = low frequency; HF = high frequency; eIF4E = eukaryotic translation initiation factor 4E; UBF = upstream binding factor; BASAL/B = 7-day period of habitual physical activity.

  • Areta, J.L., Burke, L.M., Camera, D.M., West, D.W., Crawshay, S., Moore, D.R., … Coffey, V.G. (2014). Reduced resting skeletal muscle protein synthesis is rescued by resistance exercise and protein ingestion following short-term energy deficit. American Journal of Physiology-Endocrinology and Metabolism, 306(8), E989E997. PubMed ID: 24595305 doi:10.1152/ajpendo.00590.2013

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  • Barcelos, C., Damas, F., Nobrega, S.R., Ugrinowitsch, C., Lixandrao, M.E., Marcelino Eder Dos Santos, L., & Libardi, C.A. (2018). High-frequency resistance training does not promote greater muscular adaptations compared to low frequencies in young untrained men. European Journal of Sport Science, 18(8), 10771082. PubMed ID: 29852092 doi:10.1080/17461391.2018.1476590

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  • Belloto, E., Diraison, F., Basset, A., Allain, G., Abdallah, P., & Beylot, M. (2007). Determination of protein replacement rates by deuterated water: Validation of underlying assumptions. American Journal of Physiology—Endocrinology and Metabolism, 292(5), E1340E1347. PubMed ID: 17227960 doi:10.1152/ajpendo.00488.2006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Brook, M.S., Wilkinson, D.J., Mitchell, W.K., Lund, J.N., Phillips, B.E., Szewczyk, N.J., … Atherton, P.J. (2016). Synchronous deficits in cumulative muscle protein synthesis and ribosomal biogenesis underlie age-related anabolic resistance to exercise in humans. The Journal of Physiology, 594(24), 73997417. PubMed ID: 27654940 doi:10.1113/JP272857

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burd, N.A., Holwerda, A.M., Selby, K.C., West, D.W., Staples, A.W., Cain, N.E., … Phillips, S.M. (2010a). Resistance exercise volume affects myofibrillar protein synthesis and anabolic signalling molecule phosphorylation in young men. The Journal of Physiology, 588(16), 31193130. PubMed ID: 20581041 doi:10.1113/jphysiol.2010.192856

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burd, N.A., West, D.W., Moore, D.R., Atherton, P.J., Staples, A.W., Prior, T., … Phillips, S.M. (2011). Enhanced amino acid sensitivity of myofibrillar protein synthesis persists for up to 24 h after resistance exercise in young men. Journal of Nutrition, 141(4), 568573. PubMed ID: 21289204 doi:10.3945/jn.110.135038

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burd, N.A., West, D.W., Staples, A.W., Atherton, P.J., Baker, J.M., Moore, D.R., … Phillips, S.M. (2010b). Low-load high volume resistance exercise stimulates muscle protein synthesis more than high-load low volume resistance exercise in young men. PLoS One, 5(8), e12033. PubMed ID: 20711498 doi:10.1371/journal.pone.0012033

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Damas, F., Phillips, S.M., Libardi, C.A., Vechin, F.C., Lixandrao, M.E., Jannig, P.R., … Ugrinowitsch, C. (2016). Resistance training-induced changes in integrated myofibrillar protein synthesis are related to hypertrophy only after attenuation of muscle damage. The Journal of Physiology, 594(18), 52095222. PubMed ID: 27219125 doi:10.1113/JP272472

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Dankel, S.J., Mattocks, K.T., Jessee, M.B., Buckner, S.L., Mouser, J.G., Counts, B.R., … Loenneke, J.P. (2017). Frequency: The overlooked resistance training variable for inducing muscle hypertrophy? Sports Medicine, 47(5), 799805. PubMed ID: 27752983 doi:10.1007/s40279-016-0640-8

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Davies, R.W., Bass, J.J., Carson, B.P., Norton, C., Kozior, M., Wilkinson, D.J., … Jakeman, P.M. (2020). The effect of whey protein supplementation on myofibrillar protein synthesis and performance recovery in resistance-trained men. Nutrients, 12(3), 845. PubMed ID: 32245197 doi:10.3390/nu12030845

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Figueiredo, V.C., & McCarthy, J.J. (2019). Regulation of ribosome biogenesis in skeletal muscle hypertrophy. Physiology, 34(1), 3042. PubMed ID: 30540235 doi:10.1152/physiol.00034.2018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Figueiredo, V.C., Roberts, L.A., Markworth, J.F., Barnett, M.P., Coombes, J.S., Raastad, T., … Cameron-Smith, D. (2016). Impact of resistance exercise on ribosome biogenesis is acutely regulated by post-exercise recovery strategies. Physiological Reports, 4(2), e12670. PubMed ID: 26818586 doi:10.14814/phy2.12670

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Gomes, G.K., Franco, C.M., Nunes, P.R.P., & Orsatti, F.L. (2018). High-frequency resistance training is not more effective than low-frequency resistance training in increasing muscle mass and strength in well-trained men. The Journal of Strength and Conditioning Research, 33(Suppl 1), S130S139. PubMed ID: 29489727 doi:10.1519/jsc.0000000000002559

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Grgic, J., Schoenfeld, B.J., Davies, T.B., Lazinica, B., Krieger, J.W., & Pedisic, Z. (2018). Effect of resistance training frequency on gains in muscular strength: A systematic review and meta-analysis. Sports Medicine, 48(5), 12071220. PubMed ID: 29470825 doi:10.1007/s40279-018-0872-x

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Holwerda, A.M., Paulussen, K.J.M., Overkamp, M., Smeets, J.S.J., Gijsen, A.P., Goessens, J.P.B., … van Loon, L.J.C. (2018). Daily resistance-type exercise stimulates overall muscle protein synthesis rates in vivo in young males. Journal of Applied Physiology, 124(1), 6675. PubMed ID: 28935828 doi:10.1152/japplphysiol.00610.2017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kumar, V., Atherton, P.J., Selby, A., Rankin, D., Williams, J., Smith, K., … Rennie, M.J. (2012). Muscle protein synthetic responses to exercise: Effects of age, volume, and intensity. Journals of Gerontology Series A—Biological Sciences & Medical Sciences, 67(11), 11701177. PubMed ID: 22859389 doi:10.1093/gerona/gls141

    • Crossref
    • Search Google Scholar
    • Export Citation
  • McKendry, J., Shad, B.J., Smeuninx, B., Oikawa, S.Y., Wallis, G., Greig, C., … Breen, L. (2019). Comparable rates of integrated myofibrillar protein synthesis between endurance-trained master athletes and untrained older individuals. Frontiers in Physiology, 10, 1084. PubMed ID: 31543824 doi:10.3389/fphys.2019.01084

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mitchell, C.J., Churchward-Venne, T.A., West, D.W., Burd, N.A., Breen, L., Baker, S.K., & Phillips, S.M. (2012). Resistance exercise load does not determine training-mediated hypertrophic gains in young men. Journal of Applied Physiology, 113(1), 7177. PubMed ID: 22518835 doi:10.1152/japplphysiol.00307.2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nosaka, K., Sakamoto, K., Newton, M., & Sacco, P. (2001). The repeated bout effect of reduced-load eccentric exercise on elbow flexor muscle damage. European Journal of Applied Physiology, 85(1–2), 3440. PubMed ID: 11513318 doi:10.1007/s004210100430

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Saner, N.J., Lee, M.J.C., Pitchford, N.W., Kuang, J., Roach, G.D., Garnham, A., … Bartlett, J.D. (2020). The effect of sleep restriction, with or without high-intensity interval exercise, on myofibrillar protein synthesis in healthy young men. The Journal of Physiology, 598(8), 15231536. PubMed ID: 32078168 doi:10.1113/JP278828

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Schoenfeld, B.J., Grgic, J., & Krieger, J. (2018). How many times per week should a muscle be trained to maximize muscle hypertrophy? A systematic review and meta-analysis of studies examining the effects of resistance training frequency. Journal of Sports Sciences, 37(11), 12861295. PubMed ID: 30558493 doi:10.1080/02640414.2018.1555906

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Schoenfeld, B.J., Pope, Z.K., Benik, F.M., Hester, G.M., Sellers, J., Nooner, J.L., … Krieger, J.W. (2016). Longer interset rest periods enhance muscle strength and hypertrophy in resistance-trained men. The Journal of Strength and Conditioning Research, 30(7), 18051812. PubMed ID: 26605807 doi:10.1519/JSC.0000000000001272

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Schoenfeld, B.J., Ratamess, N.A., Peterson, M.D., Contreras, B., & Tiryaki-Sonmez, G. (2015). Influence of resistance training frequency on muscular adaptations in well-trained men. The Journal of Strength and Conditioning Research, 29(7), 18211829. PubMed ID: 25932981 doi:10.1519/JSC.0000000000000970

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Shad, B.J., Thompson, J.L., Holwerda, A.M., Stocks, B., Elhassan, Y.S., Philp, A., … Wallis, G.A. (2019). One week of step reduction lowers myofibrillar protein synthesis rates in young men. Medicine & Science in Sports & Exercise, 51(10), 21252134. PubMed ID: 31083048 doi:10.1249/mss.0000000000002034

    • Crossref
    • Search Google Scholar
    • Export Citation
  • van Vliet, S., Shy, E.L., Abou Sawan, S., Beals, J.W., West, D.W., Skinner, S.K., … Burd, N.A. (2017). Consumption of whole eggs promotes greater stimulation of postexercise muscle protein synthesis than consumption of isonitrogenous amounts of egg whites in young men. The American Journal of Clinical Nutrition, 106(6), 14011412. PubMed ID: 28978542 doi:10.3945/ajcn.117.159855

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wilkinson, D.J., Franchi, M.V., Brook, M.S., Narici, M.V., Williams, J.P., Mitchell, W.K., … Smith, K. (2014). A validation of the application of D2O stable isotope tracer techniques for monitoring day-to-day changes in muscle protein subfraction synthesis in humans. American Journal of Physiology–Endocrinology and Metabolism, 306(5), E571E579. PubMed ID: 24381002 doi:10.1152/ajpendo.00650.2013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Witard, O.C., Jackman, S.R., Breen, L., Smith, K., Selby, A., & Tipton, K.D. (2014). Myofibrillar muscle protein synthesis rates subsequent to a meal in response to increasing doses of whey protein at rest and after resistance exercise. The American Journal of Clinical Nutrition, 99(1), 8695. PubMed ID: 24257722 doi:10.3945/ajcn.112.055517

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Zaroni, R.S., Brigatto, F.A., Schoenfeld, B.J., Braz, T.V., Benvenutti, J.C., Germano, M.D., … Lopes, C.R. (2019). High resistance-training frequency enhances muscle thickness in resistance-trained men. The Journal of Strength & Conditioning Research, 33(Suppl. 1), S140S151. PubMed ID: 31260419 doi:10.1519/jsc.0000000000002643

    • Crossref
    • Search Google Scholar
    • Export Citation
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