Combined short-read and long-read RNA sequencing in a murine mechanical overload model shows that aged skeletal muscle mounts a markedly diminished transcript isoform switching response compared with adult muscle, with hundreds of switching events in adult muscle versus 37 by short-read analysis and none confirmed by long-read sequencing in aged muscle. A subset of genes switched isoforms without any change in total gene expression, indicating post-transcriptional regulation that conventional gene-level analysis would miss. The loss of splicing flexibility offers a mechanistic candidate for the blunted hypertrophic adaptation characteristic of aging muscle.
Key Points
- Aged muscle showed near-absent isoform switching after acute mechanical overload
- Isoform shifts occurred without detectable gene-level expression changes
- Long-read sequencing identified Cacnb1, Naca, Psap switching only in adult muscle
Longevity Analysis
Anabolic resistance in aging muscle has been attributed largely to signaling and protein synthesis deficits; splicing inflexibility adds a layer upstream of the protein products that govern contraction, calcium handling, and repair. For practitioners, the implication is that load remains the essential stimulus, but the aged system's capacity to translate that stimulus into appropriate transcript diversity is constrained — favoring earlier, sustained, and consistently applied resistance training rather than relying on late-life intensification to recover lost adaptive range. It also argues that gene-level biomarkers of training response may systematically underreport what is happening in muscle tissue.
Original published by Wiley Aging Cell, by Pieter J. Koopmans, Abbey L. Stokes, Christopher E. Nelson, Yuan Wen, Ahmed Ismaeel, Kevin A. Murach .