Thesis
Transforming growth factor-beta-induced glycolysis in skeletal muscle cells
University of Iowa
Master of Science (MS), University of Iowa
Spring 2026
Abstract
Cancer Cachexia is a complex syndrome characterized by chronic loss of muscle mass and adipose tissue. It is associated with an increased basal metabolic rate, in part due to the increased circulation of lactate which triggers a futile Cori cycle upregulation. Lactate is thought to be produced by tumors undergoing the Warburg effect. However, the potential contribution of skeletal muscle, which produces lactate as an end-product of glycolysis, is unknown.Transforming growth factor-β (TGF-β) is a multifunctional cytokine which is involved in cancer progression, organ fibrosis, and muscle dysfunction, but its effects on muscle metabolism are poorly understood. Based on our background data showing increased glycolysis in C2C12 myotubes following TGF-β treatment, the objective of this study was to determine the mechanism of TGF-β-induced glycolysis in skeletal muscle cells and to assess its potential role in fibrotic signaling.
Using differentiated C2C12 myotubes, we evaluated gene expression, and protein levels following TGF-β treatment. Our results showed that TGF-β decreased the gene expression of the rate-limiting enzymes of glycolysis, Hexokinase 2 (HK2) and Phosphofructokinase (PFK), while Lactate Dehydrogenase (LDHA), Pyruvate Kinase Muscle Isoform 1 & 2 (PKM1 & PKM2) were unchanged. We also identified ADP-Dependent Glucokinase (ADPGK), an alternate hexokinase that catalyzes the first step of glycolysis, as being involved in the increased glycolytic flux. TGF-β treatment significantly increased ADPGK expression at both mRNA and protein levels. Importantly, siRNA-mediated knockdown of ADPGK abolished TGF-β-induced increases in glycolysis, demonstrating that ADPGK is required for this metabolic reprogramming.
Additionally, ADPGK knockdown altered the expression of glycolytic and fibrosis related genes, including Col1a1 and CTGF, suggesting a potential link between metabolic regulation and fibrotic signaling. Despite these transcriptional changes, collagen protein production was not detectable in C2C12 myotubes, suggesting that signaling regulates collagen
production rather than direct extracellular matrix protein production.
In summary, these findings demonstrate that TGF-β induces glycolytic reprogramming in skeletal muscle cells through an ADPGK-dependent mechanism. This study identifies ADPGK as a potential novel regulator of muscle metabolism and highlights a potential link between TGFβ signaling, glycolysis, and fibrosis in skeletal muscle, with implications for cancer cachexia
Details
- Title: Subtitle
- Transforming growth factor-beta-induced glycolysis in skeletal muscle cells
- Creators
- Divine Riwhie
- Contributors
- Erin Talbert (Advisor)Anna Stanhewicz (Committee Member)Vitor Lira (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Health and Human Physiology
- Date degree season
- Spring 2026
- Publisher
- University of Iowa
- Number of pages
- viii, 36 pages
- Copyright
- Copyright 2026 Divine Riwhie
- Language
- English
- Date submitted
- 04/28/2026
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (page 31-36).
- Public Abstract (ETD)
Cancer cachexia is a complex condition seen in many cancer patients, where they lose muscle mass and fat despite adequate nutrition. This leads to weakness, reduced treatment tolerance, poor survival rates, and lower quality of life. A key feature of cachexia is a change in how the body uses energy, including increased glycolysis (breakdown of glucose) and higher levels of lactate in the blood.
This study examined how transforming growth factor-beta (TGF-β), a protein which is elevated in cancer and other diseases, affects energy use in skeletal muscle. Our background data showed that TGF-β increases the rate of glucose breakdown and lactate production in C2C12 myotubes, a model of skeletal muscle cells. We surprisingly found that this increase did not occur through the usual pathways that control glucose metabolism. Instead, we identified a different enzyme, called ADP-dependent glucokinase (ADPGK), as a key driver of the metabolic changes. When we reduced ADPGK levels, the increase in glycolysis caused by TGF-β was blocked.
We also observed changes in genes linked to tissue scarring (fibrosis), although the muscle cells did not produce measurable collagen. Overall, this study shows that skeletal muscle may contribute to the increased circulating lactate in cachexia and reveals a novel way that TGF-β changes muscle metabolism. It also highlights ADPGK as a potential target for reducing lactate production and understanding muscle wasting in cancer cachexia.
- Academic Unit
- Health, Sport, and Human Physiology
- Record Identifier
- 9985177173302771
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