Chemotherapy-Induced Molecular Changes in Skeletal Muscle

Abstract

Paraneoplastic conditions such as cancer cachexia are often exacerbated by chemotherapy, which affects the patient’s quality of life as well as the response to therapy. The aim of this narrative review was to overview the body-composition-related changes and molecular effects of different chemotherapy agents used in cancer treatment on skeletal-muscle remodeling. A literature search was performed using the Web of Science, Scopus, and Science Direct databases and a total of 77 papers was retrieved. In general, the literature survey showed that the molecular changes induced by chemotherapy in skeletal muscle have been studied mainly in animal models and mostly in non-tumor-bearing rodents, whereas clinical studies have essentially assessed changes in body composition by computerized tomography. Data from preclinical studies showed that chemotherapy modulates several molecular pathways in skeletal muscle, including the ubiquitin–proteasome pathway, autophagy, IGF-1/PI3K/Akt/mTOR, IL-6/JAK/STAT, and NF-κB pathway; however, the newest chemotherapy agents are underexplored. In conclusion, chemotherapy exacerbates skeletal-muscle wasting in cancer patients; however, the incomplete characterization of the chemotherapy-related molecular effects on skeletal muscle makes the development of new preventive anti-wasting strategies difficult. Therefore, further investigation on molecular mechanisms and clinical studies are necessary.

Drug‐related sarcopenia as a secondary sarcopenia

“…The mechanism of muscle atrophy is that glucocorticoid inhibits muscle protein anabolism and enhances catabolism via its receptors in muscle, thereby inducing a decrease in muscle protein content. In fact, glucocorticoid inhibits the uptake into myofibers of amino acids necessary for muscle protein synthesis and inhibits the phosphorylation of eukaryotic translation 27,32 Abbreviations: ActRIIB, activin receptor type-2B; ALP, autophagy-lysosome pathway; IGF-1, insulin-like growth factor I; IL-6, interleukin-6; IRS-1, insulin receptor substrate-1; JAK/STAT, Janus kinase/signal transducers and activators of transcription; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappaB; PI3K, phosphatidylinositol-3 kinase; UPP, ubiquitin-proteasome pathway; ⬆, activation or increase; ⬇, inactivation or decrease; ⬆*, dysregulation of autophagy; ⬆⬇**, stabilizing or destabilizing. initiation factor 4E-binding protein 1 and the ribosomal protein S6 kinase 1, which stimulate muscle protein anabolism.…”

“…In some cases, weight loss, a frequently observed side effect of chemotherapy, is mainly related to skeletal muscle loss, which exacerbates the symptoms of cachexia induced by the malignancy itself. 27 According to one review, chemotherapy for various malignancies, with or without radiation therapy, is associated with a loss of skeletal muscle mass ranging from 2.5% to 7.8%/100 days. 28 Furthermore, this reduction in skeletal muscle mass worsens the prognosis for patients with malignant tumors.…”

“…27,30,31 Table 4 lists antineoplastic drugs that have been shown from basic or clinical studies to act directly on skeletal muscle. 27,32 Table 5 shows the mechanisms (various pathways and organelles involved) by which each antineoplastic drug induces muscle atrophy or wasting.…”

“…However, adverse reactions to chemotherapy itself occur frequently, with nausea, loss of appetite, tiredness, fatigue, and weight loss being the major adverse reactions. In some cases, weight loss, a frequently observed side effect of chemotherapy, is mainly related to skeletal muscle loss, which exacerbates the symptoms of cachexia induced by the malignancy itself 27 . According to one review, chemotherapy for various malignancies, with or without radiation therapy, is associated with a loss of skeletal muscle mass ranging from 2.5% to 7.8%/100 days 28 .…”

“…There are various factors that may contribute to muscle wasting caused by chemotherapy for malignant tumors. Although muscle wasting may be the result of chemotherapy‐related side effects such as decreased appetite, nausea/vomiting, and diarrhea, postoperative studies comparing chemotherapy with placebo have shown that chemotherapy itself directly affects muscle mass loss 29 and animal studies also support a direct effect of chemotherapy on skeletal muscle 27,30,31 …”