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

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Roberts, Michael D., Haun, Cody T., Mobley, Christopher B., Mumford, Petey W., Romero, Matthew A., Roberson, Paul A., Vann, Christopher G., McCarthy, John J.·2018·Frontiers in Physiology
DOI 10.3389/fphys.2018.00834PMC PMC6039846
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Abstract

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 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.

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  • If a high-volume mechanical stimulus induces severe microtrauma, the subsequent inflammatory response can drastically increase the non-muscle cell population within the biopsy sample, falsely elevating bulk total RNA concentration.

    “If a high-volume mechanical stimulus induces severe microtrauma, the subsequent inflammatory response can drastically increase the non-muscle cell population within the biopsy sample, falsely elevating the bulk total RNA concentration [48,73].”

    From Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators (2026) · cites this paper as [73]

    The section on inflammatory responses describes post-exercise inflammatory signaling, while the ribosome-biogenesis section describes total RNA as a surrogate for ribosome content (page numbers unavailable). Neither addresses whether high-volume exercise causes non-muscle cells to accumulate in a biopsy and falsely elevate bulk total RNA; searches for immune-cell infiltration and RNA contamination found no such passage. (LLM, conf=0.76)

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  • Cellular infiltration can lead to false-positive interpretations of muscle-specific translational capacity expansion and obscure the true magnitude of nucleolar output driving myofibrillar hypertrophy.

    “This cellular infiltration confounder can lead to systemic false-positive interpretations of muscle-specific translational capacity expansion, effectively obscuring the true magnitude of the nucleolar output driving myofibrillar hypertrophy [72,73].”

    From Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators (2026) · cites this paper as [73]

    The section “Training-Induced Ribosome Biogenesis Is Greater in High Versus Low Responders” (page unavailable) describes total muscle RNA as a surrogate for ribosome content and notes the difficulty of counting ribosomes in individual fibers. It does not say that cellular infiltration produces false-positive estimates or obscures nucleolar output; searches for infiltration and non-muscle-cell RNA found no passage addressing that claim. (LLM, conf=0.72)

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  • Chronic low-grade systemic inflammation, termed inflammaging, directly induces nucleolar stress, prioritizing stress-response protein synthesis over 45S pre-rRNA transcription.

    “chronic low-grade systemic inflammation, termed “inflammaging”, has been shown by Snijders et al. to directly induce nucleolar stress, prioritizing the synthesis of stress-response proteins over the energy-demanding transcription of massive 45S pre-rRNA precursors [73,109].”

    From Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators (2026) · cites this paper as [73]

    The section “Training-Induced Ribosome Biogenesis Is Greater in High Versus Low Responders” describes 45S pre-rRNA transcription, while “Does the Inflammatory Response to Resistance Exercise Training Limit Skeletal Muscle Growth?” discusses inflammation and muscle proteolysis. Neither section links chronic inflammation to nucleolar stress or a shift toward stress-response protein synthesis; searches for those terms and for inflammation inhibiting 45S transcription found no such passage. (LLM, conf=0.76)

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  • Marked heterogeneity in how primary studies quantify and normalize ribosomal RNA prevents performance of a precise and methodologically sound quantitative meta-analysis.

    “More importantly, the marked heterogeneity in how primary studies quantify and normalize ribosomal RNA, from whole-muscle homogenates to single-fiber transcriptomics and RNA:DNA ratios, prevents the performance of a precise and methodologically sound quantitative meta-analysis [73].”

    From Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators (2026) · cites this paper as [73]

    The section ‘Training-Induced Ribosome Biogenesis Is Greater in High Versus Low Responders’ discusses total RNA per unit of wet muscle mass as a surrogate for ribosome content and describes other detection methods. It does not say that heterogeneity in rRNA quantification or normalization prevents a sound quantitative meta-analysis; searches for meta-analysis, normalization, single-fiber transcriptomics, and RNA:DNA ratios did not establish that claim. (LLM, conf=0.72)

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Authors
Roberts, M. D., Haun, C. T., Mobley, C. B., Mumford, P. W., Romero, M. A., Roberson, P. A., Vann, C. G., & McCarthy, J. J.
Affiliations
  • Auburn University (US)
  • University of Kentucky (US)
Corresponding author
Roberts, Michael D.
ORCID
Venue
Frontiers in Physiology
Publisher
Frontiers Media SA
Published
2018-07-04
Volume
9
Pages
834-834
ISSN
1664-042X (ISSN-L)
DOI
10.3389/fphys.2018.00834
PMC
PMC6039846
OpenAlex
W2808102275
Cited by
107
References
154
Citations by year
2026: 8 · 2025: 11 · 2024: 13 · 2023: 12 · 2022: 10 · 2021: 13 · 2020: 20 · 2019: 19 · 2018: 1
FWCI
1.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Physiology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Sports Performance and Training
Keywords
skeletal muscle hypertrophy, resistance training, ribosome biogenesis, protein synthesis, satellite cell proliferation, myonuclear domain size, microRNA, insulin-like growth factor I, androgen receptor, myostatin, muscle fiber composition, protein intake, rDNA copy number, extracellular matrix, inflammation, mitochondrial function, vascular function, muscle fiber cross-sectional area, lean body mass

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