Physiological Differences Between Low Versus High Skeletal Muscle Hypertrophic Responders to Resistance Exercise Training: Current Perspectives and Future Research Directions

Numerous reports suggest there are low and high skeletal muscle hypertrophic responders following weeks to months of structured resistance exercise training (referred to as low and high responders herein). Specifically, divergent alterations in muscle fiber cross sectional area (fCSA), vastus lateralis thickness, and whole body lean tissue mass have been shown to occur in high versus low responders. Differential responses in ribosome biogenesis and subsequent protein synthetic rates during training seemingly explain some of this individual variation in humans, and mechanistic in vitro and rodent studies provide further evidence that ribosome biogenesis is critical for muscle hypertrophy. High responders may experience a greater increase in satellite cell proliferation during training versus low responders. This phenomenon could serve to maintain an adequate myonuclear domain size or assist in extracellular remodeling to support myofiber growth. High responders may also express a muscle microRNA profile during training that enhances insulin-like growth factor-1 (IGF-1) mRNA expression, although more studies are needed to better validate this mechanism. Higher intramuscular androgen receptor protein content has been reported in high versus low responders following training, and this mechanism may enhance the hypertrophic effects of testosterone during training. While high responders likely possess “good genetics,” such evidence has been confined to single gene candidates which typically share marginal variance with hypertrophic outcomes following training (e.g., different myostatin and IGF-1 alleles). Limited evidence also suggests pre-training muscle fiber type composition and self-reported dietary habits (e.g., calorie and protein intake) do not differ between high versus low responders. Only a handful of studies have examined muscle biomarkers that are differentially expressed between low versus high responders. Thus, other molecular and physiological variables which could potentially affect the skeletal muscle hypertrophic response to resistance exercise training are also discussed including rDNA copy number, extracellular matrix and connective tissue properties, the inflammatory response to training, and mitochondrial as well as vascular characteristics

LAT1 Protein Content Increases Following 12 Weeks of Resistance Exercise Training in Human Skeletal Muscle

Introduction: Amino acid transporters are essential for cellular amino acid transport and promoting protein synthesis. While previous literature has demonstrated the association of amino acid transporters and protein synthesis following acute resistance exercise and amino acid supplementation, the chronic effect of resistance exercise and supplementation on amino acid transporters is unknown. The purpose herein was to determine if amino acid transporters and amino acid metabolic enzymes were related to skeletal muscle hypertrophy following resistance exercise training with different nutritional supplementation strategies. Methods: 43 college-aged males were separated into a maltodextrin placebo (PLA, n = 12), leucine (LEU, n = 14), or whey protein concentrate (WPC, n = 17) group and underwent 12 weeks of total-body resistance exercise training. Each group\u27s supplement was standardized for total energy and fat, and LEU and WPC supplements were standardized for total leucine (6 g/d). Skeletal muscle biopsies were obtained prior to training and ~72 h following each subject\u27s last training session. Results: All groups increased type I and II fiber cross-sectional area (fCSA) following training (p \u3c 0.050). LAT1 protein increased following training (p \u3c 0.001) and increased more in PLA than LEU and WPC (p \u3c 0.050). BCKDHα protein increased and ATF4 protein decreased following training (p \u3c 0.001). Immunohistochemistry indicated total LAT1/fiber, but not membrane LAT1/fiber, increased with training (p = 0.003). Utilizing all groups, the change in ATF4 protein, but no other marker, trended to correlate with the change in fCSA (r = 0.314; p = 0.055); however, when regression analysis was used to delineate groups, the change in ATF4 protein best predicted the change in fCSA only in LEU (r2 = 0.322; p = 0.043). In C2C12 myoblasts, LAT1 protein overexpression caused a paradoxical decrease in protein synthesis levels (p = 0.002) and decrease in BCKDHα protein (p = 0.001). Conclusions: Amino acid transporters and metabolic enzymes are affected by resistance exercise training, but do not appear to dictate muscle fiber hypertrophy. In fact, overexpression of LAT1 in vitro decreased protein synthesis

A Critical Evaluation of the Biological Construct Skeletal Muscle Hypertrophy: Size Matters but So Does the Measurement

Skeletal muscle is highly adaptable and has consistently been shown to morphologically respond to exercise training. Skeletal muscle growth during periods of resistance training has traditionally been referred to as skeletal muscle hypertrophy, and this manifests as increases in muscle mass, muscle thickness, muscle area, muscle volume, and muscle fiber cross-sectional area (fCSA). Delicate electron microscopy and biochemical techniques have also been used to demonstrate that resistance exercise promotes ultrastructural adaptations within muscle fibers. Decades of research in this area of exercise physiology have promulgated a widespread hypothetical model of training-induced skeletal muscle hypertrophy; specifically, fCSA increases are accompanied by proportional increases in myofibrillar protein, leading to an expansion in the number of sarcomeres in parallel and/or an increase in myofibril number. However, there is ample evidence to suggest that myofibrillar protein concentration may be diluted through sarcoplasmic expansion as fCSA increases occur. Furthermore, and perhaps more problematic, are numerous investigations reporting that pre-to-post training change scores in macroscopic, microscopic, and molecular variables supporting this model are often poorly associated with one another. The current review first provides a brief description of skeletal muscle composition and structure. We then provide a historical overview of muscle hypertrophy assessment. Next, current-day methods commonly used to assess skeletal muscle hypertrophy at the biochemical, ultramicroscopic, microscopic, macroscopic, and whole-body levels in response to training are examined. Data from our laboratory, and others, demonstrating correlations (or the lack thereof) between these variables are also presented, and reasons for comparative discrepancies are discussed with particular attention directed to studies reporting ultrastructural and muscle protein concentration alterations. Finally, we critically evaluate the biological construct of skeletal muscle hypertrophy, propose potential operational definitions, and provide suggestions for consideration in hopes of guiding future research in this area

A Critical Evaluation of the Biological Construct Skeletal Muscle Hypertrophy: Size Matters but So Does the Measurement

Skeletal muscle is highly adaptable and has consistently been shown to morphologically respond to exercise training. Skeletal muscle growth during periods of resistance training has traditionally been referred to as skeletal muscle hypertrophy, and this manifests as increases in muscle mass, muscle thickness, muscle area, muscle volume, and muscle fiber cross-sectional area (fCSA). Delicate electron microscopy and biochemical techniques have also been used to demonstrate that resistance exercise promotes ultrastructural adaptations within muscle fibers. Decades of research in this area of exercise physiology have promulgated a widespread hypothetical model of training-induced skeletal muscle hypertrophy; specifically, fCSA increases are accompanied by proportional increases in myofibrillar protein, leading to an expansion in the number of sarcomeres in parallel and/or an increase in myofibril number. However, there is ample evidence to suggest that myofibrillar protein concentration may be diluted through sarcoplasmic expansion as fCSA increases occur. Furthermore, and perhaps more problematic, are numerous investigations reporting that pre-to-post training change scores in macroscopic, microscopic, and molecular variables supporting this model are often poorly associated with one another. The current review first provides a brief description of skeletal muscle composition and structure. We then provide a historical overview of muscle hypertrophy assessment. Next, current-day methods commonly used to assess skeletal muscle hypertrophy at the biochemical, ultramicroscopic, microscopic, macroscopic, and whole-body levels in response to training are examined. Data from our laboratory, and others, demonstrating correlations (or the lack thereof) between these variables are also presented, and reasons for comparative discrepancies are discussed with particular attention directed to studies reporting ultrastructural and muscle protein concentration alterations. Finally, we critically evaluate the biological construct of skeletal muscle hypertrophy, propose potential operational definitions, and provide suggestions for consideration in hopes of guiding future research in this area

Physiological Differences Between Low Versus High Skeletal Muscle Hypertrophic Responders to Resistance Exercise Training: Current Perspectives and Future Research Directions

Numerous reports suggest there are low and high skeletal muscle hypertrophic responders following weeks to months of structured resistance exercise training (referred to as low and high responders herein). Specifically, divergent alterations in muscle fiber cross sectional area (fCSA), vastus lateralis thickness, and whole body lean tissue mass have been shown to occur in high versus low responders. Differential responses in ribosome biogenesis and subsequent protein synthetic rates during training seemingly explain some of this individual variation in humans, and mechanistic in vitro and rodent studies provide further evidence that ribosome biogenesis is critical for muscle hypertrophy. High responders may experience a greater increase in satellite cell proliferation during training versus low responders. This phenomenon could serve to maintain an adequate myonuclear domain size or assist in extracellular remodeling to support myofiber growth. High responders may also express a muscle microRNA profile during training that enhances insulin-like growth factor-1 (IGF-1) mRNA expression, although more studies are needed to better validate this mechanism. Higher intramuscular androgen receptor protein content has been reported in high versus low responders following training, and this mechanism may enhance the hypertrophic effects of testosterone during training. While high responders likely possess “good genetics,” such evidence has been confined to single gene candidates which typically share marginal variance with hypertrophic outcomes following training (e.g., different myostatin and IGF-1 alleles). Limited evidence also suggests pre-training muscle fiber type composition and self-reported dietary habits (e.g., calorie and protein intake) do not differ between high versus low responders. Only a handful of studies have examined muscle biomarkers that are differentially expressed between low versus high responders. Thus, other molecular and physiological variables which could potentially affect the skeletal muscle hypertrophic response to resistance exercise training are also discussed including rDNA copy number, extracellular matrix and connective tissue properties, the inflammatory response to training, and mitochondrial as well as vascular characteristics

Resistance training in humans and mechanical overload in rodents do not elevate muscle protein lactylation

Although several reports have hypothesized that exercise may increase skeletal muscle protein lactylation, empirical evidence in humans is lacking. Thus, we adopted a multifaceted approach to examine if acute and subchronic resistance training (RT) altered skeletal muscle protein lactylation levels. In mice, we also sought to examine if surgical ablation-induced plantaris hypertrophy coincided with increases in muscle protein lactylation. To examine acute responses, participants’ blood lactate concentrations were assessed before, during, and after eight sets of an exhaustive lower body RT bout (n = 10 trained college-aged men). Vastus lateralis biopsies were also taken before, 3-h post, and 6-h post-exercise to assess muscle protein lactylation. To identify training responses, another cohort of trained college-aged men (n = 14) partook in 6 weeks of lower-body RT (3x/week) and biopsies were obtained before and following the intervention. Five-month-old C57BL/6 mice were subjected to 10 days of plantaris overload (OV, n = 8) or served as age-matched sham surgery controls (Sham, n = 8). Although acute resistance training significantly increased blood lactate responses ~7.2- fold (p \u3c 0.001), cytoplasmic and nuclear protein lactylation levels were not significantly altered at the post-exercise time points, and no putative lactylation-dependent mRNA was altered following exercise. Six weeks of RT did not alter cytoplasmic protein lactylation (p = 0.800) despite significantly increasing VL muscle size (+3.5%, p=0.037), and again, no putative lactylation-dependent mRNA was significantly affected by training. Plantaris muscles were larger in OV versus Sham mice (+43.7%, p \u3c 0.001). However, cytoplasmic protein lactylation was similar between groups (p = 0.369), and nuclear protein lactylation was significantly lower in OV versus Sham mice (p \u3c 0.001). The current null findings, along with other recent null findings in the literature, challenge the thesis that lactate has an appreciable role in promoting skeletal muscle hypertrophy

Protein Supplementation Throughout 10 Weeks of Progressive Run Training Is Not Beneficial for Time Trial Improvement

Introduction: Protein supplementation is proposed to promote recovery and adaptation following endurance exercise. While prior literature demonstrates improved performance when supplementing protein during or following endurance exercise, chronic supplementation research is limited.Methods: Runners (VO2peak = 53.6 ± 8.9 ml/kg/min) were counter-balanced into a placebo group (PLA; n = 8) or protein group (PRO; n = 9) based on sex and VO2peak, and underwent 10 weeks of progressive endurance training. Prior to training, body composition, blood cell differentials, non-invasive mitochondrial capacity using near-infrared spectroscopy, and a 5 km treadmill time trial (TT) were evaluated. Progressive training then commenced (5–10% increase in weekly volume with a recovery week following 3 weeks of training) whereby PRO supplemented with 25 g of whey protein following workouts and prior to sleep (additional 50 g daily). PLA supplemented similarly with a < 1 g sugar pill per day. Following training, participants were reanalyzed for the aforementioned tests.Results: VO2peak and initial 5 km TT were not significantly different between groups. PRO consumed significantly more dietary protein throughout the training period (PRO = 132 g/d or 2.1 g/kg/day; PLA = 84 g/d or 1.2 g/kg/day). Running volume increased significantly over time, but was not significantly different between groups throughout training. Blood measures were unaltered with training or supplementation. Mitochondrial capacity trended toward improving over time (time p = 0.063) with no difference between groups. PLA increased lean mass 0.7 kg (p < 0.05) while PRO experienced infinitesimal change (−0.1 kg, interaction p = 0.049). PLA improved 5 km TT performance 6.4% (1 min 31 s), while PRO improved only 2.7% (40 s) (interaction p = 0.080).Conclusion: This is the first evidence to suggest long-term protein supplementation during progressive run training is not beneficial for runners

Effects of High-Volume Versus High-Load Resistance Training on Skeletal Muscle Growth and Molecular Adaptations

We evaluated the effects of higher-load (HL) versus (lower-load) higher-volume (HV) resistance training on skeletal muscle hypertrophy, strength, and muscle-level molecular adaptations. Trained men (n = 15, age: 23 ± 3 years; training experience: 7 ± 3 years) performed unilateral lower-body training for 6 weeks (3× weekly), where single legs were randomly assigned to HV and HL paradigms. Vastus lateralis (VL) biopsies were obtained prior to study initiation (PRE) as well as 3 days (POST) and 10 days following the last training bout (POSTPR). Body composition and strength tests were performed at each testing session, and biochemical assays were performed on muscle tissue after study completion. Two-way within-subject repeated measures ANOVAs were performed on most dependent variables, and tracer data were compared using dependent samples t-tests. A significant interaction existed for VL muscle cross-sectional area (assessed via magnetic resonance imaging; interaction p = 0.046), where HV increased this metric from PRE to POST (+3.2%, p = 0.018) whereas HL training did not (−0.1%, p = 0.475). Additionally, HL increased leg extensor strength more so than HV training (interaction p = 0.032; HV \u3c HL at POST and POSTPR, p \u3c 0.025 for each). Six-week integrated non-myofibrillar protein synthesis (iNon-MyoPS) rates were also higher in the HV versus HL condition, while no difference between conditions existed for iMyoPS rates. No interactions existed for other strength, VL morphology variables, or the relative abundances of major muscle proteins. Compared to HL training, 6 weeks of HV training in previously trained men optimizes VL hypertrophy in lieu of enhanced iNon-MyoPS rates, and this warrants future research

Vivid visual mental imagery in the absence of the primary visual cortex

The role of the primary visual cortex in visual mental imagery has provided significant debate in the imagery literature. Functional neuroimaging studies show considerable variation depending on task and technique. Patient studies can be difficult to interpret due to the diverse nature of cortical damage. The type of cortical damage in patient SBR is exceedingly rare as it is restricted to the gray matter of the calcarine sulcus. In this study, we show that in spite of his near-complete cortical blindness, SBR exhibits vivid visual mental imagery both behaviorally and when measured with functional magnetic resonance imaging. The pattern of cortical activation to visual mental imagery in SBR is indistinguishable from individual sighted subjects, in contrast to the visual perceptual responses, which are greatly attenuated

Resistance training in humans and mechanical overload in rodents do not elevate muscle protein lactylation

Although several reports have hypothesized that exercise may increase skeletal muscle protein lactylation, empirical evidence in humans is lacking. Thus, we adopted a multi-faceted approach to examine if acute and subchronic resistance training (RT) altered skeletal muscle protein lactylation levels. In mice, we also sought to examine if surgical ablation-induced plantaris hypertrophy coincided with increases in muscle protein lactylation. To examine acute responses, participants’ blood lactate concentrations were assessed before, during, and after eight sets of an exhaustive lower body RT bout (n = 10 trained college-aged men). Vastus lateralis biopsies were also taken before, 3-h post, and 6-h post-exercise to assess muscle protein lactylation. To identify training responses, another cohort of trained college-aged men (n = 14) partook in 6 weeks of lower-body RT (3x/week) and biopsies were obtained before and following the intervention. Five-month-old C57BL/6 mice were subjected to 10 days of plantaris overload (OV, n = 8) or served as age-matched sham surgery controls (Sham, n = 8). Although acute resistance training significantly increased blood lactate responses ∼7.2-fold (p < 0.001), cytoplasmic and nuclear protein lactylation levels were not significantly altered at the post-exercise time points, and no putative lactylation-dependent mRNA was altered following exercise. Six weeks of RT did not alter cytoplasmic protein lactylation (p = 0.800) despite significantly increasing VL muscle size (+3.5%, p = 0.037), and again, no putative lactylation-dependent mRNA was significantly affected by training. Plantaris muscles were larger in OV versus Sham mice (+43.7%, p < 0.001). However, cytoplasmic protein lactylation was similar between groups (p = 0.369), and nuclear protein lactylation was significantly lower in OV versus Sham mice (p < 0.001). The current null findings, along with other recent null findings in the literature, challenge the thesis that lactate has an appreciable role in promoting skeletal muscle hypertrophy