Development of skeletal muscle atrophy and intermuscular adipose tissue in patients with early breast cancer treated with chemotherapy

Abstract

Background: Chemotherapy is a common therapy to treat breast cancer patients but also leads to skeletal muscle deconditioning. Skeletal muscle deconditioning is multifactorial and intermuscular adipose tissue (IMAT) accumulation is closely linked to muscle dysfunction. To date, there is no clinical study available investigating IMAT development through a longitudinal protocol and the underlying mechanisms remain unknown. Our study was dedicated to investigating IMAT content in early breast cancer patients treated with chemotherapy and exploring the subsequent cellular mechanisms involved in its development. Methods: We included thirteen women undergoing chemotherapy. Muscle biopsies and ultrasonography assessment were performed before and after chemotherapy completion. Histological and western blotting analyses were conducted. Results: We found a substantial increase in protein levels of three mature adipocyte markers (perilipin, +901%; adiponectin, +135%; FABP4, +321%; p<0.05). These results were supported by an increase in Oil red O-positive staining (+358%; p<0.05). A substantial increase in PDGFRα protein levels was observed (+476%; p<0.05) highlighting an increase in Fibro-adipogenic progenitors (FAPs) content. The cross-sectional area of the vastus lateralis muscle fibers substantially decreased (-21%; p<0.01), and muscle architecture was altered, as shown by a decrease in fascicle length (-15%; p<0.05) and a decreasing trend in muscle thickness -8%; p=0.08). Conclusions: We demonstrated both IMAT development and muscle atrophy in breast cancer patients treated with chemotherapy. FAPs, critical stem cells inducing both IMAT development and skeletal muscle atrophy, also increased, suggesting that FAPs likely play a critical role in the skeletal muscle deconditioning observed in breast cancer patients treated with chemotherapy.

Adverse effects of systemic cancer therapy on skeletal muscle: myotoxicity comes out of the closet

“…A biopsy at catheter implantation and removal resulted in minimal incremental invasiveness, as the catheter placement is inherently invasive. This serial biopsy approach allowed the investigators to record changes in mitochondrial biogenesis, mitochondrial dynamics and mitophagy [49 ▪▪ ] as well as fatty infiltration [50], specific to a treatment plan that includes anthracycline, cyclophosphamide and taxane. Although muscle mass loss was undetectable by CT when patients received this regimen [12,13 ▪ ,14] (see above), microscopic and biochemical tests reveal important changes.…”

Impact of Altered Body Composition on Clinical and Oncological Outcomes in Intrahepatic Cholangiocarcinoma

“…The animal model of Almasud et al [39] interestingly showed that adipocyte-specific genes are activated in the musculature of tumor-bearing mice. In addition, treatment with genotoxic chemotherapeutic agents leads to a larger increase in senescent cells, which in turn mediate a proinflammatory milieu and promote muscle atrophy [41]. Personalized cancer therapy in the future would therefore ideally treat cancer and adverse body composition simultaneously.…”

Age-related and cancer-related sarcopenia: is there a difference?

“…The administration of 5-fluorouracil in mice [81], was shown to disrupt skeletal muscle immune cells (CD45 þ immune cells, especially infiltrating CD11b þ Ly6cHi monocytes and CD11b þ CD68 þ macrophages) and impairs muscle repair and remodelling. The effects of a course of adriamycin-cyclophosphamide paclitaxel regimen in humans was investigated [82], through multiple sequential biopsies of the vastus lateralis muscle and showed changes in mitochondrial biogenesis, mitochondrial dynamics and mitophagy as well as fatty infiltration [83]. Interestingly such LMM was undetectable by CT [84][85][86].…”