5-Fluorouracil (
5FU) remains a first-line chemotherapeutic for several
cancers despite its established adverse side effects. Reduced blood counts with cytotoxic
chemotherapies not only expose patients to
infection and
fatigue, but can disrupt tissue repair and remodeling, leading to lasting functional deficits. We sought to characterize the impact of 5FU-induced
leukopenia on skeletal muscle in the context of remodeling. First, C57BL/6 mice were subjected to multiple dosing cycles of
5FU and skeletal muscle immune cells were assessed. Second, mice given 1 cycle of
5FU were subjected to 1.2%
BaCl2 intramuscularly to induce muscle damage. One cycle of
5FU induced significant
body weight loss, but only three dosing cycles of
5FU induced skeletal muscle mass loss. One cycle of
5FU reduced skeletal muscle CD45+ immune cells with a particular loss of infiltrating CD11b+Ly6cHi monocytes. Although CD45+ cells returned following three cycles, CD11b+CD68+ macrophages were reduced with three cycles and remained suppressed at 1 mo following
5FU administration. One cycle of
5FU blocked the increase in CD45+ immune cells 4 days following
BaCl2; however, there was a dramatic increase in CD11b+Ly6g+ neutrophils and a loss of CD11b+Ly6cHi monocytes in damaged muscle with
5FU compared with PBS. These perturbations resulted in increased
collagen production 14 and 28 days following
BaCl2 and a reduction in centralized nuclei and myofibrillar cross-sectional area compared with PBS. Together, these results demonstrate that cytotoxic
5FU impairs muscle damage repair and remodeling concomitant with a loss of immune cells that persists beyond the
cessation of treatment.NEW & NOTEWORTHY We examined the common chemotherapeutic 5-fluorouracil's (
5FU) impact on skeletal muscle immune cells and skeletal muscle repair.
5FU monotherapy decreased
body weight and muscle mass, and perturbed skeletal muscle immune cells. In addition,
5FU decreased skeletal muscle immune cells and impaired infiltration following damage contributing to disrupted muscle repair. Our results demonstrate
5FU's impact on skeletal muscle and provide a potential explanation for why some patients may be unable to properly repair damaged tissue.