Dissertation
Identification of molecular mechanisms driving skeletal muscle atrophy
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007865
Abstract
Skeletal muscle atrophy is a prevalent and debilitating condition, which can be triggered by diverse stresses including aging, muscle disuse, malnutrition, critical illness, and many chronic illnesses. Despite broad clinical significance, the molecular basis of skeletal muscle atrophy remains poorly understood and no pharmacological interventions currently exist to counteract it. This thesis investigates the molecular mechanisms driving skeletal muscle atrophy, with a particular focus on the role of the stress-induced transcriptional regulator Activating transcription factor 4 (ATF4) and the ATF4-target gene Cdkn1a/p21.
In skeletal muscle, ATF4 expression is necessary and sufficient for skeletal muscle atrophy, as the ATF4 protein can rapidly promote skeletal muscle atrophy in young animals deprived of adequate nutrition or activity. Using muscle specific ATF4 knockout (ATF4 mKO) mice, we found that ATF4 expression in skeletal muscle fibers contributes to the loss of skeletal muscle mass and function that occurs during normal aging. Furthermore, ATF4 contributes to the repression of certain anabolic mRNAs and the induction of certain senescence-associated mRNAs that are characteristic of muscle aging. Using unbiased transcriptomic analyses of muscles from ATF4 mKO mice, we identified 30 ATF4-dependent skeletal muscle mRNAs involved in stress signaling and translational control that may mediate these effects.
Utilizing in vivo experimental models, we characterized one of these ATF4-dependent mRNAs, which encodes the protein Cyclin-dependent kinase inhibitor 1a (Cdkn1a/p21). We demonstrate that p21 is a direct ATF4-target gene in skeletal muscle fibers and is a pivotal mediator of ATF4-induced muscle atrophy. In the muscles of young healthy mice, forced p21 expression is sufficient to induce skeletal muscle atrophy, as well as decrease mitochondrial content and function. Mechanistically, p21 interacts with multiple cyclin-CDK complexes in skeletal muscle, with the inhibition of CDK1 being central to p21-mediated muscle atrophy. Consistent with this, targeted inhibition of CDK1 within skeletal muscle fibers recapitulates many of the cellular and molecular effects of p21 over-expression.
Collectively, these studies suggest that the ATF4/p21/CDK1 pathway is an important mediator of muscle atrophy and weakness. This advances our understanding of the molecular etiology of muscle atrophy and opens new areas of investigation into the causes and treatment of a condition that affects hundreds of millions of people worldwide.
Details
- Title: Subtitle
- Identification of molecular mechanisms driving skeletal muscle atrophy
- Creators
- Matthew James Miller
- Contributors
- Christopher M Adams (Advisor)Peter M Snyder (Committee Member)Chad E Grueter (Committee Member)Aloysius J Klingelhutz (Committee Member)Michael G Anderson (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Genetics
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007865
- Publisher
- University of Iowa
- Number of pages
- xvii, 126 pages
- Copyright
- Copyright 2025 Matthew James Miller
- Language
- English
- Date submitted
- 04/01/2025
- Description illustrations
- illustrations, graphs, tables
- Description bibliographic
- Includes bibliographical references (pages 111-126).
- Public Abstract (ETD)
- Skeletal muscle atrophy is a common and debilitating condition that represents a major public health challenge. Muscle atrophy is not limited to a specific region or demographic, but spans across ethnicities and socioeconomic classes, affecting hundreds of millions of people worldwide, particularly older adults. A loss of muscle size and strength can occur slowly over years due to factors such as normal aging and chronic illness, or rapidly over days to weeks in cases of sustained nutrient deficiency or prolonged muscle disuse. Despite widespread clinical significance, there are currently no pharmacologic therapies to prevent or reverse muscle atrophy, largely because the molecular basis of this condition remains incompletely understood. In this thesis, I investigated the molecular mechanisms driving muscle atrophy. Specifically, I identified a stress-induced pathway driven by the transcriptional regulatory protein Activating transcription factor 4 (ATF4) as central to the loss of muscle mass that occurs during aging. I demonstrate that the p21 gene is a direct ATF4 target in muscle, and that activation of p21 promotes skeletal muscle atrophy. I further show that inhibition of Cyclin-dependent kinase 1 (CDK1) is one of the mechanisms by which ATF4- mediated p21 expression reduces muscle fiber size, as well as mitochondrial content and function. Collectively, my studies characterize molecular mechanisms involved in the loss of skeletal muscle mass and open new areas of investigation into the causes and treatment of muscle atrophy.
- Academic Unit
- Craniofacial Anomalies Research Center; Interdisciplinary Graduate Program in Genetics
- Record Identifier
- 9984830924702771
Metrics
6 Record Views