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.

Keywords: cancer patients; chemotherapy; molecular changes; muscle wasting; skeletal muscle.

Figure 1

Signaling pathways modulated by chemotherapy in skeletal muscle. Doxorubicin decreases IRS1, NF-κB, and PGC1α expression, which consequently increases the expression of UPP (atrogin-1 and MuRF-1 ligases), and in mitochondria increases ROS generation. ROS levels also increased following doxorubicin plus dexamethasone treatment. Cisplatin increases phosphorylation of SMAD2, Mstn, and FOXO3 and induces atrogin-1 and MuRF-1 mRNA expression, thereby reducing Akt levels. When combined with gemcitabine, besides up-regulating atrogin-1, MuRF-1, Mstn, and FOXO3, cisplatin also stimulates ActRIIB. Oxaliplatin enhances STAT phosphorylation and activates both UPP and APL by increasing the expression of atrogin-1, MuRF-1, and Atg genes such as LC3 and BNIP3. 5-fluorouracil diminishes Akt levels and increases both p38 phosphorylation and NF-κB levels. FOLFIRI and FOLFOX act similarly, both decreasing PGC1-α protein levels and increasing ROS levels; however, FOLFIRI also reduces Akt levels. Legend: Cis: cisplatin; Dox: doxorubicin; C+G: cisplatin plus gemcitabine; Oxa: oxaliplatin; D+D: doxorubicin plus dexamethasone; Cis+5FU+Leu: cisplatin plus 5-fluorouracil plus leucovorin. Blue: modulation of animal studies; pink: modulation of in vitro studies. Created with BioRender.com (accessed on 16 February 2023).