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Peer-reviewedCC BYAging cell

A Hypertrophic Stimulus Drives Age-Dependent Transcript Isoform Switching With and Without Differential Gene Expression in Skeletal Muscle.

  • Pieter J Koopmans1,2
  • Abbey L Stokes3
  • Christopher E Nelson1,3
  • Yuan Wen4,5
  • Ahmed Ismaeel6
  • Kevin A Murach1,2,7,8,9
9 affiliations
  1. 1Cell and Molecular Biology Graduate Program, University of Arkansas, Fayetteville, Arkansas, USA.
  2. 2Molecular Muscle Mass Regulation (M3R) Laboratory, Department of Health, Human Performance, & Recreation, University of Arkansas, Fayetteville, Arkansas, USA.
  3. 3Department of Biomedical Engineering, University of Arkansas, Fayetteville, Arkansas, USA.
  4. 4Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.
  5. 5Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.
  6. 6Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA.
  7. 7NextGen Precision Health Initiative, University of Missouri, Columbia, Missouri, USA.
  8. 8Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, USA.
  9. 9Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, USA.
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Abstract

Aged skeletal muscle has a reduced ability to adapt to hypertrophic stimuli concomitant with dysregulation across several molecular layers. Whether altered RNA splicing associates with impaired adaptive potential is not well studied. We hypothesized that aging disrupts the splicing response to involuntary muscle mechanical loading. Using deep short-read Illumina RNA-sequencing (SRS, 60 million read pairs) and third generation Oxford Nanopore long-read RNA-sequencing (LRS) combined with a murine model of acute muscle mechanical overload (MOV), we illustrate how aged muscle has a reduced or possibly delayed potential for isoform switching in response to stress. SRS identified hundreds of genes with isoform switching events in adult MOV relative to sham but only 37 in aged MOV. LRS identified 19 genes (including Cacnb1, Naca, Psap) with true isoform switching in adult MOV and none in aged MOV. A subset of genes showed significant isoform switching without corresponding changes in overall gene expression, suggesting post-transcriptional regulation in response to MOV. These data highlight the importance of analyzing the transcriptome at the isoform level to uncover transcript diversity and "unseen genes" that may have unique functions and mechanisms influencing hypertrophic adaptations.

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Cite

BibTeXRIS
BibTeX
@article{koopmans2026hypertrophic,
  title = {{A Hypertrophic Stimulus Drives Age-Dependent Transcript Isoform Switching With and Without Differential Gene Expression in Skeletal Muscle.}},
  author = {Pieter J Koopmans and Abbey L Stokes and Christopher E Nelson and Yuan Wen and Ahmed Ismaeel and Kevin A Murach},
  journal = {Aging cell},
  year = {2026},
  month = oct,
  doi = {10.1111/acel.70761},
  url = {https://europepmc.org/article/MED/42876144},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - A Hypertrophic Stimulus Drives Age-Dependent Transcript Isoform Switching With and Without Differential Gene Expression in Skeletal Muscle.
AU  - Pieter J Koopmans
AU  - Abbey L Stokes
AU  - Christopher E Nelson
AU  - Yuan Wen
AU  - Ahmed Ismaeel
AU  - Kevin A Murach
PY  - 2026
DA  - 2026/10/01
JO  - Aging cell
DO  - 10.1111/acel.70761
UR  - https://europepmc.org/article/MED/42876144
AB  - Aged skeletal muscle has a reduced ability to adapt to hypertrophic stimuli concomitant with dysregulation across several molecular layers. Whether altered RNA splicing associates with impaired adaptive potential is not well studied. We hypothesized that aging disrupts the splicing response to involuntary muscle mechanical loading. Using deep short-read Illumina RNA-sequencing (SRS, 60 million read pairs) and third generation Oxford Nanopore long-read RNA-sequencing (LRS) combined with a murine model of acute muscle mechanical overload (MOV), we illustrate how aged muscle has a reduced or possibly delayed potential for isoform switching in response to stress. SRS identified hundreds of genes with isoform switching events in adult MOV relative to sham but only 37 in aged MOV. LRS identified 19 genes (including Cacnb1, Naca, Psap) with true isoform switching in adult MOV and none in aged MOV. A subset of genes showed significant isoform switching without corresponding changes in overall gene expression, suggesting post-transcriptional regulation in response to MOV. These data highlight the importance of analyzing the transcriptome at the isoform level to uncover transcript diversity and "unseen genes" that may have unique functions and mechanisms influencing hypertrophic adaptations.
SN  - 1474-9718
SN  - 1474-9726
ER  -