The Role of Fibro-Adipogenic Progenitors in Radiation-Induced Muscle Pathology

Abstract

Globally, cancer is one of the leading causes of mortality, with an estimated 18.1 million cancer cases, 10 million deaths, and 1.9 million new cases diagnosed in 2020 (Sung et al., 2021). However, during the past several decades, cancer survival has improved such that 82% of children and >2/3 of adults diagnosed with cancer will survive beyond five years (World Health Organization (WHO) - Childhood Cancer, 2021). Skeletal muscle atrophy and fibrosis are long-term adverse effects experienced by 80% of cancer survivors for which there is no available therapy (Paulino, 2004). These long-term consequences are related to the toxicity from the cancer treatment, leading to alterations in skeletal muscle function which can lead to comorbidities and increased mortality among cancer survivors (Paulino, 2004; Williams et al., 2016). Thus, novel approaches to address the long-term effects of cancer therapy on skeletal muscle are critically needed. Exercise training is a potential non-pharmacological strategy that improves common cancer- and treatment-related side effects (Mustian et al., 2012). Specifically, exercise programs that combine resistance and endurance training (RET) have been shown to improve muscle strength and cardiovascular fitness in cancer survivors (Tong et al., 2020). The mechanisms responsible for these effects remain unknown. The remarkable plasticity of skeletal muscle relies primarily on muscle stem (satellite) cells (MuSCs) (Lepper et al., 2011) that are regulated, in part, by muscle-resident stromal cells (Bentzinger et al., 2013). These different stromal cell types, including: vascular endothelial cells (ECs), immune cells, and mesenchymal progenitors, also known as fibro-adipogenic progenitors (FAPs), create the muscle stem cell niche (Yin et al., 2013). FAPs possess a dual role as they are involved in skeletal muscle maintenance and regeneration by secreting pro-myogenic trophic factors (Biferali et al., 2019; Joe et al., 2010; Uezumi et al., 2010; Wosczyna et al., 2019), but also contribute to fibrotic and fatty tissue accumulation in chronic degenerative conditions (Uezumi et al., 2010). The divergent features of FAPs highly depend on signals they receive from their microenvironment (Giuliani et al., 2021); however, FAP's contribution to cancer treatment-induced muscle pathology in cancer survivors remains unknown. The overall objective of this thesis is to begin to develop an understanding of the role of FAPs in cancer treatment-induced muscle pathology and to determine if RET represents an effective therapy to prevent the long-term muscle defects of juvenile cancer plus therapy.