Table 1.
Summary of mechanisms discussed in this review
| Mechanism | Responses to Mechanical Overload | Knowledge of Current Role(s) | Knowledge Gaps |
|---|---|---|---|
| mTORC1 signaling | ↑↑↑ | mTORC1 signaling is critically involved with skeletal muscle hypertrophy through increased translation initiation and/or elongation. | Further interrogation of the upstream activating signals during mechanical overload |
| mTORC1-independent signaling | ↑↑↑ | MAPK signaling and other mTORC1-independent signals are transiently activated after a bout of resistance exercise to presumably affect aspects of transcription and translation. | Further elucidating the role MAPK signaling and other mTORC1-independent signals (e.g., YAP and TRIM28 phosphorylation) have in promoting skeletal muscle hypertrophy |
| Ribosome biogenesis | ↑↑↑ | Increased translational capacity | Determining whether ribosome specialization occurs with overload and, if so, determining whether this is a critical aspect of hypertrophy |
| Satellite cells | ↑↑↑ | Myonuclear accretion via fusion, muscle repair, and nonfusion roles | In humans, validating preliminary animal findings suggesting that satellite cells coordinate extracellular matrix adaptations during overload; also examining whether hypertrophy can proceed in the absence of satellite cell-mediated myonuclear accretion in humans with certain diseases where satellite cell counts are reduced (e.g., MYMK mutations); finally, determining how satellite cell fusion alters molecular processes in myofibers (single-cell studies) or myofiber morphology |
| Genetic variants | Inherently present; no changes to overload | Various single-candidate polymorphism studies show small hypertrophic advantages with certain genotypes. | Performing deep sequencing efforts to identify novel variants and adopting statistical approaches to examine the combinatorial effects of multiple variants |
| Epigenetic alterations | ↑↑↑ and ↓↓↓ | Methylation changes occur across hundreds of genes in the nuclear genome, and preliminary evidence suggests demethylation of mitochondrial genome with resistance training in humans. | Determining whether gene-specific methylation responses to overload are needed for hypertrophy to occur; further determining whether prolonged DNA demethylation during periods of mechanical overload confers more robust skeletal muscle hypertrophy |
| Muscle proteolysis | ↑↑↑ early into training, but response subsides with increased training status. | Potentially needed for removing damaged proteins and organelles after initial stages of resistance training | Determining which proteolytic system(s) is primarily responsible for adaptive responses early (i.e., weeks) and later (i.e., months to years) into training; additionally, determining whether these proteolytic systems are required for muscle hypertrophy to occur in response to loading paradigms and/or whether synchronization between synthesis and proteolysis directs the degree of hypertrophy |
| Myostatin markers | ↓↓↓ | Numerous lines of evidence suggest that resistance training acutely and transiently decreases muscle MSTN mRNA levels. | Elucidating how MSTN pathway signaling (e.g., SMAD2/3 phosphorylation and the mRNA expression of downstream targets) is transiently affected during the initial and later stages of overload and whether these events are critically involved in the hypertrophic response |
| Extracellular matrix remolding | ↑↑↑ | Markers of extracellular matrix remodeling are altered during periods of resistance training, but much of this work has been confined to mRNAs. | Broadening the scope of extracellular matrix remodeling markers during resistance training studies to determine whether remodeling is required or merely coincides with skeletal muscle hypertrophy |
| Angiogenesis | ↑↑↑ | Preliminary evidence suggests that capillary number per fiber prior to resistance training is associated with hypertrophic response to training. | Determining whether the magnitude of angiogenesis induced by resistance training (and/or enhanced microvessel function) enhances muscle hypertrophy |
| Muscle microRNA expression | ↑↑↑ and ↓↓↓ | Genes involved with IGF1/PI3K/AKT/mTOR signaling are directly and/or indirectly regulated by various miRNAs that are altered in response to overload. | Moving beyond microRNA-omics-based studies in humans to show a core set of microRNAs involved with or needed for skeletal muscle hypertrophy |
| Testosterone signaling | ??? | Transient postexercise responses in circulating testosterone concentrations do not correlate with intracellular anabolic signaling events (e.g., mTORC1 signaling or muscle protein synthesis) and hypertrophy. However, muscle hormone receptor protein content modestly correlates with anabolic outcomes in some studies. | Determining whether androgen DNA binding is altered during periods of overload and which of the identified hormone receptor-affected genes are involved with skeletal muscle hypertrophy |
| Inflammation through prostaglandin signaling | ↑↑↑ | Coincides with robust elevations in protein synthesis and satellite cell proliferation during in the initial phases of resistance training. | Determining whether certain aspects of inflammation (e.g., EP and FP receptor signaling) are needed for, or merely coincide with, skeletal muscle hypertrophy |
| β-Adrenergic signaling through endogenous catecholamines | ??? | The administration of β-adrenergic receptor agonists promotes skeletal muscle hypertrophy. | Determining whether intrinsic β-adrenergic receptor signaling via endogenous catecholamines, in part, promotes skeletal muscle hypertrophy during periods of mechanical overload |
| Angiotensin II signaling | ??? | Preliminary animal evidence suggested angiotensin II signaling is involved with overload-induced skeletal muscle hypertrophy. However, follow-up animal studies suggest angiotensin II signaling may blunt hypertrophic responses, and human data in this area are mixed. | Determining whether intrinsic angiotensin II signaling blunts, enhances, or does not affect hypertrophic outcomes in humans |
| Mitochondrial biogenesis | ↑, ↓, or ↔ | The increase in mitochondrial volume density may precede or concomitantly occur with muscle hypertrophy. | Demonstrating whether an expansion of the mitochondria is required for myofiber hypertrophy, or whether mitochondrial biogenesis, mitochondrial expansion, and myofiber hypertrophy merely coincide with one another |
| Other bioenergetic adaptations | ↑↑↑ | Resistance training can promote differential metabolic adaptations in skeletal muscle. | Determining whether metabolic adaptations (e.g., enhanced glycolytic flux) provide skeletal muscle with substrates needed for cell growth |
| Muscle circadian transcriptome | ??? | The oscillation of core clock genes in muscle transcriptionally regulates hundreds of genes related to metabolism, protein turnover, ribosome biogenesis, and other processes. | Determining whether the muscle circadian transcriptome is altered (or disrupted) during periods of overload; if so, is this an involved mechanism with molecular adaptations (e.g., ribosome biogenesis or the altered expression of metabolic genes)? |
| Microtubule networks, and myonuclear and RNA trafficking | ??? | Studies suggest that 1) microtubule-dependent RNA transport from myonuclei to ribosomes is essential for the translation process to occur and 2) myonuclear trafficking to focal injury sites occurs through microtubules. | Determining whether microtubule network expansion scales with hypertrophy and if this process is needed to support RNA and myonuclear trafficking |
| Microbiome alterations | Minimal changes in bacterial species diversity | Preliminary evidence suggests that resistance training may not drastically alter diversity metrics in the gut microbiome. | Determining whether metabolites produced by the gut microbiome change in response to training; if so, do they act as signals to affect anabolic signaling pathways? |
↑↑↑ or ↓↓↓, several independent laboratories have shown increases or decreases in markers associated with mechanism; ↑, ↓, or ↔, less evidence supports the mechanism being involved in mechanical overload-induced skeletal muscle hypertrophy; ???, involvement in mechanical overload-induced skeletal muscle hypertrophy has not been well elucidated relative to other discussed mechanisms. IGF1, insulin-like growth factor 1; PI3K, phosphatidylinositol 3-kinase; MSTN, myostatin; mTOR, mammalian/mechanistic target of rapamycin; mTORC1, mammalian/mechanistic target of rapamycin complex 1.