How Chemotherapy Wastes Muscle and Fogs the Brain: A New Muscle–Brain Framework Points to Exercise

Chemotherapy saves lives, but it increasingly appears to exact a hidden toll on two tissues that most patients and even many clinicians rarely connect: skeletal muscle and the brain. A comprehensive review published in the Journal of Cachexia, Sarcopenia and Muscle synthesizes clinical and preclinical evidence showing that the same drugs designed to halt tumor growth also damage mitochondria in muscle fibers and neurons, driving both muscle wasting and the cognitive impairment often called chemobrain. The authors propose a unified muscle–brain mechanistic framework in which damaged muscle acts as an endocrine organ gone awry, flooding the bloodstream with inflammatory signals that ultimately reach the hippocampus, and they argue that exercise, through its effects on muscle-derived signaling molecules, may be the most practical countermeasure available.

The scale of the problem is substantial. Global demand for first-course chemotherapy is projected to rise from 9.8 million patients annually in 2018 to 15 million by 2040, making long-term treatment side effects a growing public health concern. Among the most consequential is loss of skeletal muscle, which has now been linked to poorer survival and higher recurrence across multiple cancer types. In patients with metastatic colorectal cancer, those who lost more than 9 percent of skeletal muscle mass during chemotherapy had significantly reduced survival, with muscle loss independently predicting outcome. Breast cancer patients receiving neoadjuvant chemotherapy who lost more than 3 percent of their skeletal muscle index showed poorer disease-free survival than those who maintained muscle mass.

The mechanism behind this myotoxicity appears to center on mitochondria. Because chemotherapeutic agents work by damaging DNA and halting cell division, they cannot distinguish cancer cells from healthy ones with high metabolic demand. Skeletal muscle, which contains greater mitochondrial density than most other somatic tissues and makes up roughly 40 percent of body mass in healthy-weight individuals, is particularly vulnerable. Biopsy samples from breast cancer patients after neoadjuvant chemotherapy showed significant reductions in mitochondrial function, measured by citrate synthase and VDAC, alongside increased apoptotic cells. Animal studies reinforce the picture: doxorubicin injection reduced NADH- and FADH2-supported respiration in rodent muscle while increasing hydrogen peroxide emission, and chemotherapy-treated models showed suppressed mitochondrial biogenesis and mitophagy regulators including PGC-1α, cytochrome c and Parkin.

Intriguingly, the classic molecular markers of muscle wasting, such as MuRF-1, myostatin and Activin A, were largely unchanged in chemotherapy-treated animal models, suggesting that mitochondria rather than canonical proteolysis pathways are the critical therapeutic target. Additional mechanisms are emerging, including anabolic resistance that blunts the muscle’s response to nutrition and exercise, and post-transcriptional regulation: in cachectic colon-26 tumor-bearing mice, 5-fluorouracil worsened muscle loss via miR-351-3p-mediated inhibition of ERK2 signaling, and suppressing this microRNA partially restored fiber size.

The cognitive side of the framework rests on a striking paradox. Many commonly used chemotherapeutic agents cross the blood–brain barrier poorly, so direct drug toxicity to neurons cannot fully explain chemobrain. Instead, the authors endorse a peripheral-to-central model: chemotherapy-induced mitochondrial dysfunction in peripheral tissues elevates circulating oxidative stress and pro-inflammatory cytokines, which in turn amplify endogenous inflammation and reactive oxygen species production in the hippocampus. This feedback loop damages neuronal mitochondria, triggering apoptosis and degeneration. Animal studies support the chain of events, showing that doxorubicin raises TNF-α and oxidative damage markers in both plasma and hippocampus, impairs mitochondrial respiration and membrane potential in brain tissue, and reduces neurogenesis markers, all accompanied by measurable deficits in spatial and working memory.

Clinical evidence aligns with these findings. A recent meta-analysis found that one in three breast cancer patients receiving chemotherapy develops clinically significant cognitive impairment, and a cohort of 503 breast cancer patients documented new-onset cognitive impairment in 20 percent within the first year, with chemotherapy associated with more than double the risk. Proton magnetic resonance spectroscopy in patients has revealed reduced N-acetylaspartate and total creatine in the posterior cingulate gyrus, indicating compromised neuronal integrity, and these metabolite changes correlated with cognitive test performance across domains including verbal memory, processing speed and executive function.

Against this backdrop, exercise emerges as the most consistently effective intervention for skeletal muscle health in patients with cancer, and possibly for the brain as well. Randomized trials in breast, ovarian and gastrointestinal cancer patients undergoing chemotherapy show that combined aerobic and resistance training increases muscle mass, strength and VO2 max. Notably, one trial found that high-intensity interval training during chemotherapy preserved muscle fiber cross-sectional area, capillarization and mitochondrial content, evidenced by elevated citrate synthase activity and PINK1, while usual-care patients declined. Exercise also reduced plasma protein carbonyls, 8-hydroxy-2′-deoxyguanosine, interferon-γ and interleukin-1β in other trials, directly targeting the oxidative and inflammatory mediators implicated in the muscle–brain loop.

Preclinical work extends these benefits to cognition. Exercised rodents given doxorubicin or cisplatin showed improved spatial, working and short-term memory alongside restored hippocampal BDNF and TrkB signaling, enhanced neurogenesis, reduced apoptotic markers and improved neuronal mitochondrial function, with lower hydrogen peroxide emission and inflammatory cytokines in both brain and plasma. Clinical trials in cancer survivors report improvements in working memory, episodic memory, executive function and cerebral blood flow after aerobic training, and one study found exercise appeared especially beneficial for patients experiencing high fatigue, possibly because its anti-inflammatory effects attenuated inflammation-related cellular swelling in the hippocampus.

The framework’s most novel element concerns myokines, the signaling molecules skeletal muscle releases during contraction. The authors highlight BDNF and irisin as particularly compelling candidates for muscle–brain communication. BDNF, produced by contracting muscle, supports mitochondrial content and quality through the AMPK–PGC-1α pathway and protects neurons from oxidative damage while stimulating mitochondrial biogenesis via PGC-1α. Irisin, cleaved from FNDC5, activates the cAMP/PKA/CREB pathway in neurons through integrin αV/β5, promotes hippocampal neurogenesis, and has been shown in animal models to reduce ROS production and NFκB-driven inflammation. The proposed PGC-1α–FNDC5/irisin–BDNF axis offers a plausible route by which contracting muscle could directly nourish the brain, though the authors caution that myokines are one component within a complex network that also includes lactate and cathepsin B, and their specific roles during chemotherapy remain incompletely characterized.

For clinical practice, the authors suggest that cardiorespiratory fitness, tracked through VO2 max given its linear relationship with muscle mitochondrial content, should be a primary therapeutic target alongside preservation of muscle mass. Based on evidence from older adults, potentially beneficial prescriptions include roughly 60 minutes of continuous moderate-intensity aerobic exercise at 60 to 70 percent of VO2 max, or 30 to 40 minutes of interval work with peak bouts at 70 to 80 percent, complemented by resistance exercise on alternating days to counteract muscle loss. Because most chemotherapy trials have used mixed-mode programs, disentangling the specific contributions of each modality remains a research priority. Future translational studies, the authors argue, should quantify the relative contributions of mitochondrial adaptation, oxidative stress reduction, inflammatory regulation and myokine signaling to exercise-induced cognitive benefits, paving the way for exercise medicine that simultaneously improves survival through muscle health and quality of life through a protected brain.

Subject of Research: Mechanisms linking chemotherapy-induced skeletal muscle mitochondrial dysfunction to cognitive impairment and the protective role of exercise-induced myokines

Article Title: Chemotherapy‐Induced Skeletal Muscle Dysfunction and Cognitive Impairment: A Muscle‐Brain Mechanistic Framework With Implications for Exercise Oncology

Article References: Ahn, S., Kim, J.-S., Galvao, D. A., Taaffe, D. R., Yoon, D. H., McIntyre, C., Schofield, C., Chang, Y. J., Min, J., Song, W., & Newton, R. U. (2026). Chemotherapy‐Induced Skeletal Muscle Dysfunction and Cognitive Impairment: A Muscle‐Brain Mechanistic Framework With Implications for Exercise Oncology. Journal of Cachexia, Sarcopenia and Muscle, 17(5), Article e70394. https://doi.org/10.1002/jcsm.70394

Image Credits: AI Generated

DOI: 10.1002/jcsm.70394

Keywords: chemotherapy, chemobrain, skeletal muscle, mitochondria, cognitive impairment, exercise oncology, myokines, BDNF, irisin, oxidative stress, inflammation, cancer survivorship