Chemotherapy May Trigger Muscle Loss Even at Lower Doses

Chemotherapy agents may be triggering muscle loss in people with cancer starting at lower doses than previously reported, according to an in vitro experiment from researchers at Penn State University.

This study was published in the American Journal of Physiology – Cell Physiology.

Chemotherapy and Muscle Loss

Previous research has found that treatment with chemotherapeutic agents impacts mitochondria within muscle cells, triggering the loss of muscle tissue due to oxidative stress, according to the study authors.

In this study, Gustavo Nader, PhD, and colleagues, studied how three chemotherapy drugs dosed at levels too low to trigger oxidative stress impacted cultured muscle cells.

“We chose to do this study in cultured cells because in a living organism, chemotherapy also affects nonmuscle cells like those in the pancreas and liver, which can then trigger their own processes that can also affect muscle cells,” Dr. Nader said. “We wanted a very controlled environment with only the muscle cells and chemotherapy drugs so we can examine very precisely how they interact.”

According to the results, these anti-cancer drugs interfered with the process behind building new muscle.

“For a long time, people thought the problem with chemo and muscle loss was an issue with degrading the proteins that already existed in the muscle,” said Dr. Nader, via a press release. “So, a lot of research and treatments in the past had the goal of preventing protein degradation. But our study points to there also being a problem with protein synthesis, or the building of new muscle proteins, as well.”

Identifying Mechanisms of Muscle Loss

To understand how chemotherapeutic agents directly impact muscle protein synthesis, the investigators first identified the mechanisms of protein synthesis impairment due to mitochondrial involvement. They found that elevations in mitochondrial reactive oxygen species (ROS) result in “protein synthesis deficits, reduced ribosomal (r)RNA levels and increased rRNA oxidation.”

Then, the team assessed how chemotherapeutic agents impact protein synthesis without detectable elevations in ROS. They assessed the impact of three drugs: paclitaxel, doxorubicin, and marizomib. These drugs were applied to the cultured cells for up to 48 hours. Even at doses that did not trigger elevations in ROS, all three drugs demonstrated diminished protein synthesis and ribosomal capacity and impaired rRNA gene transcription.

“These results indicate that while oxidative stress disrupted protein synthesis by compromising ribosome quantity and quality, chemotherapeutic agents at sub-ROS doses also impaired protein synthesis and ribosomal capacity by reducing rDNA transcription,” wrote the authors. “Therefore, chemotherapeutic agents can negatively modulate myotube protein synthesis in a ROS-independent manner by altering the capacity for protein synthesis.”

Considerations for Cancer Treatment

According to Dr. Nader, the results of this study have the potential to change how healthcare providers think about the impact of chemotherapy on the body.

“Eventually, it may be that the implementation of cancer treatments should consider that even at low doses that do not cause oxidative stress, some chemotherapy drugs may still promote the loss of muscle tissue,” he said. “The tumor is already making you weak, it’s contributing to the loss of muscle mass, and the chemo drugs are helping the tumor to accomplish that.”

“If you’re still receiving chemotherapy while going through an exercise rehabilitation program, it’s possible that chemo could impede your progress,” said Dr. Nader. “During exercise interventions, the muscles need to make ribosomes, which then build new proteins. But if the drug is blocking that, the rehab might not be successful. The implications of this work could be huge, and I think we’re beginning to see the tip of the iceberg.”