An article was recently published in Nutrition Reviews which aimed to summarize the current literature on the effects of fructose on reactive oxygen species (ROS) production and mitochondrial dysfunction in various tissues, particularly skeletal muscle, and identify research gaps for which future endeavors should address.
First, reviewers provided an overview of the metabolic effects of fructose in the skeletal muscle after uptake by glucose transporter 5 (GLUT5). Reviewers cited various in vitro studies which demonstrated mitochondrial dysfunction, apoptosis, oxidative stress, and accumulation of acylcarnitine in skeletal muscles following fructose uptake. Reviewers then cited a number of in vivo studies which provided 25% of energy requirements from fructose. Together, these studies reportedly demonstrated increased blood pressure, increased cardiac output, increased heat rate, increased de novo lipogenesis, increased low density lipoprotein, and elevated levels of uric acid, gamma-glutamyl transferase, and retinol-binding protein 4.
Next, reviewers looked more specifically at the in vivo literature which describes the effects of fructose on mitochondrial reactive oxygen species in skeletal muscle. One human study found that supplementing participants with fructose at 3g/kg body weight per day for 9 weeks resulted in increased oxidative stress as evidence by elevated levels of thiobarbituric acid-reactive substances and protein carbonylation. Furthermore, mitochondrial gene expression and mitochondrial respiration were attenuated following fructose treatment. Researchers concluded from this data that fructose contributes to mitochondrial dysfunction. Similarly, another human study found that a diet high in fructose and sucrose promoted elevated levels of hydrogen peroxide and protein carbonylation. Moreover, the researchers noticed a reduced mRNA expression of cytochrome C-oxidase and peroxisome proliferator-activated receptor-γ coactivator 1α.
A recent in vitro study revealed that fructose treatment of skeletal muscles resulted in “increased mitochondrial ROS and reduced antioxidant enzymes. There were also significant declines in mitochondrial DNA content, adenosine triphosphate (ATP) synthesis, mitochondrial membrane potential, and activities of mitochondrial respiratory complexes. Results from all these studies indicate that fructose leads to excessive ROS production in the skeletal muscle and has deleterious effects on skeletal muscle mitochondria.”
The mechanisms for these observed effects has yet to be elucidated; here, reviewers offer various theories. The first theory is that fructose-induced hepatic de novo lipogenesis results in elevated lipid circulation and this lipid infiltrates muscle cells creating a “toxic” effect by promoting mitochondrial dysfunction and reducing ATP synthesis, oxygen consumption, and oxidative phosphorylation. The next theory reviewers offer is that fructose consumption leads to a rise in uric acid and uric acid promotes ROS production in a dose dependent manner. Furthermore, researchers claim it has been shown that hyperuricemia upregulates excretion of transforming growth factor (TGF-β1), a cytokine which regulates cell proliferation and differentiation, and circulating TGF-β1 is known to stimulate ROS production via activation of Nox4. Additionally, the reviewers noted an in vitro study which exposed human hepatocytes to TGF-β1 and showed increased levels of Nox4, ROS, caspase activation, apoptosis, and cell death.
Reviewers concluded, “Excessive consumption of fructose increases ROS production in skeletal muscle, leading to impaired cellular function…Since fructose increases the production of uric acid, which circulates throughout the body, its detrimental effects in skeletal muscle might likewise be attributed to TGF-β1 and Nox4. Further investigations are recommended to test this hypothesis in skeletal muscle.”