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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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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 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]
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In the citing paper
“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]
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“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]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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]
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Roberts, M. D., McCarthy, J. J., Hornberger, T. A., Phillips, S. M., Mackey, A. L., Nader, G. A., Boppart, M. D., Kavazis, A. N., Reidy, P. T., Ogasawara, R., et al. (2023) · Physiological Reviews · doi:10.1152/physrev.00039.2022 · Cited by 214
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Colenso‐Semple, L. M., D’Souza, A. C., Elliott-Sale, K. J., & Phillips, S. M. (2023) · Frontiers in Sports and Active Living · doi:10.3389/fspor.2023.1054542 · Cited by 201
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Metadata
- 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)
- 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
- gold
- doi.org
- 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
- Health Sciences › Nursing › Nutrition and Dietetics › 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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