Written by Michael J. Rudolph, Ph.D.
19 November 2020


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By Michael J. Rudolph, Ph.D.

Senior Science Editor


Normal cellular function involves metabolic processes, such as the production of energy, that generate all sorts of stress on the cell including the production of very reactive compounds known as reactive oxygen species (ROS). These ROS can wreak havoc on the cell’s molecular machinery, causing irreparable oxidative damage. Moreover, during strenuous exercise the rate of ROS production increases tremendously, primarily due to greater energy demands put on the muscle cell during exercise. 


In order to mitigate oxidative damage caused by ROS, various antioxidants are utilized that can chemically react with the ROS and prevent them from damaging biomolecules within the body. For instance, the well-known antioxidant vitamin C mitigates many negative effects associated with oxidative damage from ROS by chemically reacting with and inactivating the ROS. Yet beyond the well-documented health benefits associated with antioxidant use, recent evidence shows that consuming antioxidants weakens muscular growth and performance because ROS have also been shown, within certain concentrations, to be useful signaling molecules that enhance muscle function and size.  


ROS and Enhanced Energy in Muscle Cells

Exercise increases ROS production, subsequently promoting the expression of specific proteins within the cell that are able to deal with these highly reactive compounds and their associated oxidative stress. As a result, antioxidant consumption prevents the activation of these important protein molecules, which promote useful adaptations in the body. For instance, antioxidant consumption has been shown to diminish the upregulation of powerful antioxidant enzymes such as the superoxide dismutase, which directly consumes ROS and diminishes the damage associated with ROS. 


In addition, other proteins that enhance the cell’s ability to diminish ROS-related stress, in alternative ways, are also upregulated by the presence of ROS. These proteins initiate the production of the cellular organelle known as the mitochondrion. The mitochondrion, the well-known powerhouse of the cell, aerobically produces cellular energy. During exercise, an increased energy demand somewhat overwhelms the mitochondrial energy-producing system, causing an increased production and leakage of ROS from the mitochondria into the cell. These greater ROS levels stimulate the cell to increase the number of mitochondria in the muscle cell1,2 by causing the amplification of the protein PGC1-alpha. Consequently, PGC1-alpha directly upregulates mitochondrial production. 


The increase in mitochondrial number allows the mitochondrial system to match the increased energy demands on the cell, which diminishes the further production of ROS. More mitochondria also increases the muscle cell’s ability to produce energy, which leads to greater muscular performance and growth. Therefore, antioxidant depletion of ROS will prevent this increase in energy production within the muscle cell, reducing optimal muscle function during exercise. 


Negative Influence of Vitamins C and E

Many scientific reports support the concept that exercise-induced ROS production contributes to exercise-associated muscle adaptations. A common approach in many of these scientific studies is to get rid of the effects from exercise-induced ROS production in muscle by giving the test subjects antioxidants. For example, a scientific investigation by Gomez-Cabrera et al.3 concluded that antioxidant supplementation can slow down important training adaptations in human muscle. Specifically, Gomez-Cabrera et al. reported that the administration of the antioxidant vitamin C prevented exercise-induced expression of PGC-1 alpha in muscle cells, which also disrupted mitochondrial production in muscle. Furthermore, the administration of vitamin C also prevented exercise-induced expression of several antioxidant enzymes in muscle.


In another study by Ristow et al.4, 40 people performed a defined exercise regimen for four weeks. All test subjects went to the gym five days a week, where they did 40 minutes of circuit training and 20 minutes of biking. Twenty subjects received 1,000 milligrams of vitamin C and 400 units of vitamin E while the other half received a placebo. The study ultimately demonstrates that high doses of vitamin C and vitamin E alleviate the ability of ROS to generate the production of PGC1-alpha and new mitochondria.


As many previous studies have shown that ROS can trigger insulin resistance, Ristow et al. also wanted to investigate whether vitamin C and E consumption could prevent ROS-initiated insulin resistance. Yet instead of vitamin C and E protecting against insulin resistance, they demonstrated that the antioxidant consumption decreased ROS levels, subsequently decreasing mitochondrial levels. Since mitochondria are the place in the cell where fat is burned, the lower mitochondrial levels repressed the body’s ability to burn body fat, generating greater body fat. Because more body fat leads to insulin insensitivity, the test subjects actually showed a decreased level of insulin signaling.


Collectively, these results conclude that ROS production enhances the muscle cell’s ability to produce energy and that antioxidant consumption negatively influences this augmented capability.


Vitamin C Delays Muscle Recovery From Exercise

Intense weightlifting or exercise stresses the muscle cell, producing muscle damage that requires a substantial recovery period to reestablish muscle function. There is emerging evidence proposing that ROS assist in the recovery process, however all of the details have not been fully established. In order to further the understanding that ROS play in muscle recovery, a study by Close et al.5 investigated the effects of vitamin C supplementation on ROS production and the length of recovery necessary to completely recuperate from downhill running. During the study, some of the subjects received one gram of vitamin C for 14 days post-downhill running, while the control group received a placebo. The exercise regimen resulted in delayed onset muscle soreness associated with downhill running and impaired muscle function in both groups, although a delayed recovery was noted in the group supplemented with vitamin C. Because vitamin C has been shown to attenuate ROS production following exercise, the authors concluded that vitamin C supplementation inhibited the recovery of muscle function.


Antioxidants Can Inhibit Muscle Protein Synthesis

IGF-1 is known to promote protein synthesis within the muscle cell, promoting muscle hypertrophy.6 Low levels of ROS have been show to positively influence IGF-1 signaling.7 This positive influence on IGF-1 signaling by ROS mainly occurs because ROS can directly inhibit the action of a class of enzymes known as phosphatases – that typically reverse the natural activation of many different signaling cascades, such as the IGF-1-driven protein synthesis pathway. Therefore, ROS inactivation of the phosphatase that turns off IGF-1-driven protein synthesis ultimately generates greater muscle protein synthesis and muscle growth. Interestingly, this study also shows that higher ROS levels inhibit IGF-1 signaling. These results suggest that antioxidant use, leading to a lower level of ROS production, should be the most beneficial environment for muscle growth.


In conclusion, correct amounts of ROS present in the cell appear to positively contribute to muscle growth and performance – and just like many other things in life, too much of a good thing can be detrimental. Therefore, a precise antioxidant regimen should produce the optimal amount of ROS within the muscle cell, facilitating muscle size and strength.


For most of Michael Rudolph’s career he has been engrossed in the exercise world as either an athlete (he played college football at Hofstra University), personal trainer or as a research scientist (he earned a B.Sc. in Exercise Science at Hofstra University and a Ph.D. in Biochemistry and Molecular Biology from Stony Brook University). After earning his Ph.D., Michael investigated the molecular biology of exercise as a fellow at Harvard Medical School and Columbia University for over eight years. That research contributed seminally to understanding the function of the incredibly important cellular energy sensor AMPK – leading to numerous publications in peer-reviewed journals including the journal Nature. Michael is currently a scientist working at the New York Structural Biology Center doing contract work for the Department of Defense on a project involving national security.  




1. Irrcher I, Ljubicic V, et al. Interactions between ROS and AMP kinase activity in the regulation of PGC-1alpha transcription in skeletal muscle cells. Am J Physiol Cell Physiol 2009;296(1): p. C116-23.


2. Jackson MJ. Skeletal muscle aging: role of reactive oxygen species. Crit Care Med 2009;37(10 Suppl): p. S368-71.


3. Gomez-Cabrera MC, et al. Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr 2008;87(1): p. 142-9.


4. Ristow M, et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A, 2009;106(21): p. 8665-70.


5. Close GL, et al. Ascorbic acid supplementation does not attenuate post-exercise muscle soreness following muscle-damaging exercise but may delay the recovery process. Br J Nutr 2006;95(5): p. 976-81.


6. Louis M, et al. Creatine increases IGF-1 and myogenic regulatory factor mRNA in C(2)C(12) cells. FEBS Lett, 2004;557(1-3): p. 243-7.


7. Papaconstantinou J. Insulin/IGF-1 and ROS signaling pathway cross-talk in aging and longevity determination. Mol Cell Endocrinol 2009;299(1): p. 89-100


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