Skeletal muscle loss is a critical manifestation of cancer cachexia (Argiles et al., 2010). While our mechanistic understanding of cancer-induced muscle wasting continues to develop and potential therapeutic targets to treat the condition have been identified, both the complexity of the underlying disease and the multiple mechanisms responsible for the maintenance of skeletal muscle homeostasis have clouded our ability to understand the primary drivers of this catabolic condition. While there may still be hope for a “master regulator” of cancer-induced muscle atrophy (Lecker et al., 2004), the heterogeneity of cancer, pre-existing conditions of the patient, and equivocal findings between preclinical cachexia models have led to a host of potential drivers of the cachectic condition that are too broad to describe in detail here. However, this topic has been extensively reviewed (Argiles et al., 2014, 2015; Carson et al., 2016; Vanderveen et al., 2017; Baracos, 2018). Skeletal muscle responds to a multitude of systemic cues that are vital for whole body homeostasis, and the muscle fiber responds to global stimuli including disuse, increased activity, aging, and metabolic mediators (Atherton et al., 2016), which can all be altered with cancer and chemotherapy. Furthermore, due to these varied physiological and functional demands, muscle fibers differ in contractile and metabolic properties, and these properties can impact how the muscle fiber responds to the cancer environment (Carson et al., 2016; Vanderveen et al., 2017). The complexity of the muscle’s physiological response to cancer and chemotherapy is also impacted by the myofiber’s interaction with the ECM, vasculature, and response to local inflammation, which is examined in this review.

Despite the identified complexities in understanding muscle mass regulation with cancer, muscle mass maintenance requires a balanced regulation of protein turnover, which is maintained by anabolic and catabolic signaling pathways. Cancer induces fundamental disruptions to the homeostatic regulation of the protein turnover that has negative consequences for skeletal muscle function and cellular metabolism (Baracos et al., 2018; Counts et al., 2020). Cachexia drives overall muscle mass loss even with adequate nutrient intake (Fearon et al., 2012a; Porporato, 2016), and results in suppressed protein synthesis and/or increased degradation. Muscle protein synthesis and breakdown can be regulated by various stimuli including nutrient availability, hormones, mechanical loading, and metabolic stress, which can all be disrupted by cancer and potentially chemotherapy (Glass, 2005; Powers et al., 2005; Zhang et al., 2007; Egerman and Glass, 2014). Active areas of investigation for the disruption of protein turnover with cancer have focused on excessive protein breakdown by the ubiquitin proteasome system (UPS) and disrupted autophagy regulation (McClung et al., 2010; White et al., 2011; Fearon et al., 2012b; Penna et al., 2013; Luo et al., 2014; Aversa et al., 2016). Critical intracellular regulator networks in skeletal muscle exert tight control of these processes but can be disrupted by cancer and chemotherapy. This skeletal muscle regulatory nexus involves Akt, mTORC1, FOXO3A, and AMPK signaling, which responds to growth factors, mechanical stimuli (i.e., stretch and contraction), cellular energy levels (AMP: ATP), nutrients (amino acids), and inflammation (Carson, 1997; Carson and Wei, 2000; Glass, 2005; Judge et al., 2014). These mechanisms exert control over cell growth through regulation of protein synthesis (e.g., transcription and translation), protein degradation (e.g., UPS) autophagy, and metabolism (Laplante and Sabatini, 2009). Disruption to this signaling network in cachectic skeletal muscle also has been linked to cancer-induced mitochondrial dysfunction (Carson et al., 2016; Vanderveen et al., 2017, 2019; Fix et al., 2019). Muscle mitochondrial dysfunction continues to be extensively investigated as an underlying mechanism for the initiation and progression of cancer-induced muscle wasting. However, understanding how cancer disrupts the normal dynamic regulation of muscle protein turnover remains an active area of inquiry.

Cancer-induced systemic inflammation and the increased production of specific cytokines have been extensively investigated as an underlying driver of cancer cachexia (Argilés et al., 2019). Both adipose tissue and skeletal muscle catabolism can be induced by exacerbated inflammation. Examination of cachectic cancer patients and preclinical models of cachexia has identified interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), TNF-like inducer of apoptosis (TWEAK), TNF receptor (TNFR)-associated factor 6 (TRAF6), interferon gamma (INF-γ), and leukemia inhibitory factor (LIF) as mediators of cancer-induced muscle wasting (White et al., 2013; Hetzler et al., 2015; Zimmers et al., 2016; Yakovenko et al., 2018; Argilés et al., 2019). These cytokines can induce several intracellular pathways including the nuclear factor-κB (NF-κB) pathway, p38 mitogen-activated protein kinase (MAPK) pathway, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Notwithstanding the identification of several different inflammatory mediators in cachexia, we lack understanding of how these signaling pathways interact or overlap with other physiological signaling within the muscle microenvironment to regulate muscle catabolism with cancer. Due to this complexity barriers remain for implementing therapeutic strategies that target an individual signaling cascade to preserve skeletal muscle mass in the cancer patient. Moreover, there are currently no FDA-approved treatments for cancer cachexia. That said, there remains strong therapeutic potential for nutritional, anti-inflammatory, and lifestyle management strategies to mitigate cachexia severity and improve patient life quality.

Cachexia’s prevalence with cancer is often dependent on cancer type and stage of the disease; however, the functional deficits with chemotherapy are consistent and pervasive (Barreto et al., 2016a; Bozzetti, 2020). Along with nausea, emesis, and anorexia, weakness and fatigue remain among the most commonly reported off-target effects of chemotherapy (Dahele et al., 2007). Our understanding of chemotherapy’s deleterious off-target effects on skeletal muscle has improved over the last decade highlighting a key role for metabolic and DNA/cell stress (Gilliam et al., 2009; Barreto et al., 2016b; Morton et al., 2019; Sougiannis et al., 2019). Targeting the generation of mitochondrial reactive oxygen species (ROS), by exercise or antioxidants, has shown promise in mitigating Doxorubicin (DOX)-induced skeletal muscle dysfunction (Smuder, 2019; Montalvo et al., 2020), and targeting the activation of MAPKs with ACVR2B/Fc and MEK1 inhibitors has been proposed to alleviate 5-FU induced mitochondrial dysfunction (Barreto et al., 2016b, 2017). Inflammatory signaling has been demonstrated to regulate chemotherapy-induced E3 ligase activation through modulating TNF-α (Gilliam et al., 2009). Interestingly, while conclusive mechanisms involving intrinsic skeletal muscle inflammatory signaling with chemotherapy are lacking, leukopenia with chemotherapy has been well-established (Kvinnsland, 1999; Yamanaka et al., 2007; Shitara et al., 2009; Baechler et al., 2010; Han et al., 2012; Abraham et al., 2015). This naturally invites intrigue into understanding how chemotherapy-induced immunosuppression can converge with cancer-associated chronic inflammation to disrupt the skeletal muscle microenvironment, which can lead to wasting, reduced life quality, poor treatment outcomes, and subsequent reduced survival. While again there are currently no approved treatments for chemotherapy’s off-target effects on muscle, there remains similar strong therapeutic potential for nutritional, anti-inflammatory, antioxidant, and/or lifestyle management to mitigate chemotherapy-induced toxicities.

The identification of immune checkpoints, specifically PD-1/PDL1 and CTLA-4, has led to the use of specific inhibitors, which have greatly improved cancer therapies (Haanen and Robert, 2015). These drugs improve the anti-tumor capacity of T-cells and potentially natural killer (NK) cells by blocking the ligand/receptor binding induced by cancer cells that cause T-cell inactivation (Curran et al., 2010; Pesce et al., 2019). Similar to other cancer treatments, patients receiving immune check point inhibitors (ICPIs) that suffer from cachexia have reduced survival when compared to patients who maintain their weight (Chu et al., 2020; Roch et al., 2020). Whether ICPIs can induce cachexia has not been established; however, body weight loss in aged mice with mesothelioma tumors was exacerbated by immunotherapy, but whole body macrophage depletion reduced tumor mass and body weight loss (Duong et al., 2018). As using ICPIs become increasingly more common as a cancer treatment, understanding the impact of cachexia and the role of ICPI in cachexia progression remains an intriguing area for future inquiry.

Developing an understanding of the distinct contributions of cancer and chemotherapy to muscle wasting and dysfunction has been at the forefront of cachexia related mechanistic inquiry; however, understanding the potential synergism or negation of specific mechanisms with both cancer and chemotherapy would improve our understanding of cancer patient’s condition. To date, few studies have directly investigated the effect of cancer and chemotherapy on skeletal muscle which leads to cachexia. Barreto et al. (2016a) identified the common pathways activated by C26-induced cachexia and chemotherapeutic Folfiri [5-fluorouracil (5FU), leucovorin, irinotecan]-induced cachexia. This study highlighted a common downregulation of metabolic and structure proteins with particularly striking changes to mitochondrial function (Barreto et al., 2016a). Interestingly, only Folfiri induced neurological damage, while only C26 was associated with exercise intolerance. Others have demonstrated that TNF-α plays a key role in cancer and DOX-induced skeletal muscle dysfunction (Hardin et al., 2008; Gilliam et al., 2009, 2011). While disrupted protein turnover has been a central regulator of cancer-induced cachexia (White et al., 2013; Montalvo et al., 2018; Counts et al., 2020), there is little evidence to suggest chemotherapy impacts muscle in this same way.

While the primary focus of this review is to highlight the impact of monocytes, neutrophils, and T-cells on the skeletal muscle microenvironment, other immune cells involved in cancer’s immune disruptions should not be neglected as their role in skeletal muscle homeostasis is merely less understood. These cells include, but are not limited to, B-cells, NK cells, myeloid derived suppressor cells (MDSC), and mast cells (Murphy and Weaver, 2016). The role of these various cell types in the pathogenesis of DMD has been reviewed (Madaro and Bouche, 2014). B-cells were recently shown to modulate muscle weakness during dermatomyositis through the regulation of IFNγ (Radke et al., 2018). Mast cells aggregate and proliferated in sites of muscle necrosis following damage and can restore vascular permeability during myositis (Gorospe et al., 1996; Yokota et al., 2014); however, little is known about their role with muscle wasting with cancer and chemotherapy. Interestingly, MDSCs were shown to be increased with cancer thought to contribute to global disruptions in energy metabolism contributing to cachexia progression (Cuenca et al., 2014). A correlative increase of IL-17 and MDSCs were both associated with nutritional impairments with gastrointestinal cancer which was proposed to contribute to cachexia (Yazawa et al., 2013). Furthermore, the metabolic cost of myelopoiesis, mainly increased MDSCs, may also contribute to the metabolic abnormalities seen with cancer and chemotherapy (Sica and Strauss, 2017).

The myofiber response to cancer and the cachectic environment is considered to be central to understanding muscle wasting regulation. However, there is an emerging consideration for tumor derived factors and inflammatory mediators to go beyond targeting the myofiber directly (Biswas and Acharyya, 2020). The cachectic environment has the potential to also indirectly disrupt myofiber homeostasis through the altered regulation of other cell types in the muscle microenvironment (Talbert and Guttridge, 2016), highlighting a need to delineate the capacity for cancer and chemotherapy to disrupt myofiber interactions with other cell types in muscle (Figure 2). Furthermore, each cell type has a critical function within the skeletal muscle microenvironment, involving ECM remodeling and angiogenesis, which are established components of muscle plasticity in response to regeneration from injury, growth, aging, overload-induced hypertrophy, and exercise (Dennis et al., 2009; Morgan and Partridge, 2020). Since skeletal muscle fiber nuclei are post-mitotic, the role of the satellite cell in aging and overload hypertrophy has been actively investigated for over 30 years. This line of inquiry includes the role of myonuclear apoptosis in sarcopenia and myonuclear accretion in hypertrophy myofibers (McCarthy et al., 2011; Fry et al., 2014). As skeletal muscle remodeling is a critical property of muscle and is thought to be a continuous process over an individual’s life span, there is growing interest in how aging, disuse, cancer, and chemotherapy treatments can disrupt remodeling processes in skeletal muscle, which could serve to exacerbate the development and progression of cachexia.

The ECM surrounding each muscle fiber can contain an assortment of fibroblasts, endothelial cells, immune cells, and satellite cells which are located beneath the basal lamina (Forcina et al., 2019). These cells have individual and coordinated roles in the response to local inflammation that accompanies muscle remodeling to damage, increased use/activity, and overload (Morgan and Partridge, 2020). Furthermore, changes within the ECM serve to initiate intracellular myofiber signaling through receptors on the sarcolemma in response to damage and mechanical stretch (Carson and Wei, 2000). The ECM is a rich source of growth factors and cytokines that can be released to regulate myofiber proteostasis and metabolic function (Forcina et al., 2019). Muscle fibers interact with the fibrous elements of the matrix through integrin receptors to sense mechanical signaling, and shifts in the expression of fibrous matrix proteins such as collagens have potential to alter intracellular signaling in muscle fibers (Carson and Wei, 2000). Thus, the cancer systemic environment has the potential to dysregulate myofiber gene expression and metabolic signaling through alterations to the ECM. Muscle fibrosis and dysregulation of the ECM has been reported in cachectic skeletal muscle from pancreatic cancer patients (Judge et al., 2018; Nosacka et al., 2020), and fibrosis can negatively impact myofiber growth and healing from damage (Bedair et al., 2007; Li et al., 2016a). Muscle inflammatory processes are established modulators of the ECM for healing and wound repair and also critical for muscle remodeling to exercise and overload. In fact, disruptions to IL-6 expression during overload-induced hypertrophy and during the recovery from disuse-induced muscle atrophy in mice can alter the hypertrophy response, collagen composition within the ECM, and muscle fibrosis in mice (White et al., 2009; Washington et al., 2011). Furthermore, during the initiation of compensatory overload-induced hypertrophy in mice an inflammatory and ECM gene expression is strongly induced (Carson et al., 2002). These observations demonstrate the complexity of the ECM response and local inflammation, since they drive hypertrophy with overload and healing from damage, but are also implicated in cancer-induced muscle wasting (Forcina et al., 2019). To this end, local inflammatory responses are subjected to precise temporal regulation and if this response is altered muscle remodeling can be either attenuated or blocked (Howard et al., 2020), and further research is warranted to determine if cancer can disrupt the temporal aspects of local inflammation needed for successful remodeling. For example, inflammatory signaling can impact several cell types located in the muscle microenvironment leading to altered myofiber protein synthesis (Gao et al., 2017) and mitochondrial quality control (Gomez-Cabrera et al., 2016), which are known drivers of muscle wasting with cancer. In this section, three important cell types are highlighted that interact with the myofiber within the muscle microenvironment and their potential role in cancer and chemotherapy-induced muscle wasting is emphasized.

The role of the satellite cell in skeletal muscle physiological and biological responses to a variety of conditions, stimuli, and disease states has been extensively investigated since being first discovered by Mauro in 1961 (Mauro, 1961; Penna et al., 2010; He et al., 2013). The satellite cell is located between the myofiber sarcolemma and basal lamina and is not easily distinguished from a myonuclei with light microscopy. These cells remain in a quiescent state, but can be activated to proliferate and differentiate by a variety of growth factors and mitogenic stimuli (Bischoff, 1986a,b). Satellite cell differentiation can involve either fusion with existing myofibers to allow for myonuclear accretion or the formation of de novo myotubes. Therefore, the satellite cell has been extensively examined as a myogenic stem cell in skeletal muscle critical for muscle repair and growth processes. Both the regulation and disruption of satellite cell number, activation, proliferation potential, and differentiation have been widely investigated for 60 years (Forcina et al., 2019). Interestingly, one of the earliest described inducers of satellite cell proliferation was FGF, and this activation was also linked to damage disruption of the muscle ECM (Bischoff, 1986a,b). This line of inquiry coincides with investigation to this day involving satellite cell control by their microenvironment and the cells that are at the source of these mitogenic factors. There has been increasing interest in understanding the cancer environment’s effect on satellite cell activity, which could directly impact cachectic muscle’s diminished capacity for muscle regeneration (Schwarzkopf et al., 2006; Penna et al., 2010; He et al., 2013; Talbert and Guttridge, 2016). Deficits in the capacity for myogenesis, which is needed for successful muscle regeneration, have been reported in skeletal muscle from preclinical cachexia models and cancer patients, and involve an inability of satellite cells to effectively differentiate to complete the regenerative process (Penna et al., 2010; He et al., 2013). Due to the importance of the successful myogenic response in muscle regeneration, signaling pathways disrupting satellite cell activity have been actively investigated as potential therapeutic targets for cancer-induced muscle wasting (Schwarzkopf et al., 2006; He et al., 2013; Cerquone Perpetuini et al., 2018; Costamagna et al., 2020; Schmidt et al., 2020). To this end, skeletal muscle satellite cell differentiation has been reported to be rescued in colon-26 induced cachexia in mice through the inhibition or ERK signaling (Penna et al., 2010), and more recently IL-4 administration (Costamagna et al., 2020). Pax7 is a positive regulator of satellite cell proliferation, which has been reported to be disrupted in cachectic muscle from mice and cancer patients (He et al., 2013); dysregulation of Pax7 in cachectic muscle was driven by aberrant NF-κΒ signaling induced by circulating tumor derived factors. Wnt signaling is an established regulator of muscle satellite cell activity through the expression of myogenic regulatory factors and increased Wnt7a in colon-26 induced cachexia in mice can increase muscle regeneration by the improvement of muscle satellite regulation of differentiation and the induction of anabolic signaling through Akt/mTORC1 (Schmidt et al., 2020). Interestingly, mathematical modeling of colon-26 induced cachexia in mice recently predicted that blocking the myostatin/activin A pathway could attenuate cancer-induced muscle mass loss through the restoration of functional satellite cell differentiation (Farhang-Sardroodi and Wilkie, 2020). Depending on the extent of the damage, successful muscle regeneration including the initiation and resolution of local inflammatory processes involves infiltrating monocytes, resident MΦs, neutrophils, and T-cells (Morgan and Partridge, 2020). Local inflammatory responses are subjected to precise temporal regulation and if this response is altered muscle remodeling can be either attenuated or blocked (Howard et al., 2020), and further research is warranted to determine if cancer can disrupt the temporal aspects of local inflammation that contribute to disrupted satellite cell regulation of differentiation in cachectic muscle.

The satellite cell has been hypothesized to have critical roles in post-natal muscle growth, overload-induced hypertrophy, capacity of muscle regeneration after damage, and the development of sarcopenia. The development of modern molecular biology tools has shed light on the role of satellite depletion on these processes (McCarthy et al., 2011; Fry et al., 2014), but interesting gain of function experiments remain elusive. While the role of the satellite cell with some types of overload-induced growth and sarcopenia remains equivocal (Murach et al., 2018), the satellite cell has an established role in muscle regeneration from injury. Interestingly, there is emerging evidence that satellite cells have a regulatory role in ECM during overload-induced hypertrophy (Murach et al., 2018). Additionally, MΦs have been demonstrated to interact with satellite cells to regulate myogenesis (Dort et al., 2019). Pro-inflammatory monocytes and MΦs release cytokines, IL-6 and TNF-α, to stimulate satellite cell proliferation and inhibit differentiation until switching to an M2-like phenotype to promote differentiation and fusion (Arnold et al., 2007). T-cells have been demonstrated to maintain satellite cells myogenic potency in vitro (Fu et al., 2015), while T-cell deficient mice had reduced satellite cell proliferation contributing to blunted repair (Castiglioni et al., 2015; Deyhle and Hyldahl, 2018). There is significant interest in muscle microenvironment changes that occur with aging that could alter satellite cell regulation and serve to impede muscle regeneration from injury (Lee et al., 2019). Satellite cell number and activity are thought to be impacted by aging, and other regulators of satellite cell function such as the immune response are also aging targets (Forcina et al., 2019). Therefore, the impact of age on satellite cell activity could be a factor in the development and progression of cachexia due to the advanced age of many patients having cancers that are associated with high cachexia incidence. These facts could directly impact our current mechanistic understanding of cancer cachexia, as preclinical modeling that account for the effects of sarcopenia and aging on the skeletal muscle microenvironment are needed to answer these critical questions.

Fibroblasts have a central role in the formation and remodeling of the skeletal muscle ECM which provides stability for the myofiber, blood vessels, and nerves (Chapman et al., 2016; Mendias, 2017). Fibroblasts aid in the synthesis and deposition of collagen, which predominate skeletal muscle connective tissues. Matrix metalloproteinases (MMPs) are largely responsible to the breakdown and deposition of collagen in the ECM. MMPs are released by immune cells, myofibers, satellite cells, epithelial cells, and fibroblasts themselves and are transcriptionally regulated by classic cytokine signaling cascades (Thomas et al., 1998; Liu et al., 2006; Phatharajaree et al., 2007; Yndestad et al., 2007; Iyer et al., 2016). These cells release MMPs to degrade several components of the cytoskeleton and stimulate de novo collagen deposition by the fibroblast (Sundararaj et al., 2009). Additionally, fibroblasts and satellite cells coordinate during skeletal muscle regeneration to limit fibrosis and promote healthy hypertrophic repair (Murphy et al., 2011).

The role of several immune cell types and inflammatory mediators in skeletal muscle fibroblast proliferation and collagen deposition has been extensively studied due to their integral functions in tissue repair (Van Linthout et al., 2014). In addition to providing structural support, fibroblasts are sensitive to mechanical stretch and maintain the ECM by aiding in the breakdown and synthesis/deposition of skeletal muscle collagens (Tomasek et al., 2002). Additionally, this mechanical sensitivity allows fibroblasts to release their own cytokines/chemokines for early neutrophil recruitment to aid in the breakdown of the damaged ECM through the action of MMPs, collagenases, and elastases (Baici et al., 1982; Kim and Luster, 2015); however, this mechanistic link in skeletal muscle requires additional work. On the other hand, innate immune cells can induce re-expression of fetal genes, activation of MMPs, fibro-adipogenic progenitor (FAP) differentiation, proliferation of fibroblasts, and myofibroblast formation (Tomasek et al., 2002; Gentek and Hoeffel, 2017; Tidball, 2017). Pro-inflammatory cytokines TNF-α, IL-6, and IL-1β are produced and secreted by Th cells and M1-like MΦs to stimulate fibroblast proliferation, while the anti-inflammatory TGFβ and IL-10 are predominately produced by Tregs and M2-like MΦs to stimulate fibroblast collagen synthesis and deposition (Van Linthout et al., 2014; Jablonski et al., 2015). M2-like MΦ release of arginase 1 (Arg1) also can stimulate fibroblast proliferation through the production of polyamines from arginase metabolism (Tidball, 2017). While the proper coordination of fibroblast proliferation and collagen formation is necessary for healthy skeletal muscle repair and remodeling, both reduced or exacerbated fibroblast activity can result in fibrosis and reduced skeletal muscle plasticity and overall functional capacity (Chapman et al., 2016). Fibrosis during the progression of cancer cachexia has received significant attention due to its role in reduced skeletal muscle plasticity and the loss of strength disproportionate to mass (Judge et al., 2018; Ramage and Skipworth, 2018); however, evidence of impaired regeneration and increased fibrosis in cachectic skeletal muscle is limited to cancer type and severity of the disease (Nosacka et al., 2020).

Endothelial cells are cells that are associated with blood vessels, which vascularize skeletal muscle. Intuitively, skeletal muscle vascularization plays central roles in nutrient transportation (e.g., glucose delivery and CO₂ removal) and global/systemic communication (e.g., hormones and cytokines/myokines). When necessary, the myofiber, resident fibroblasts, and/or resident immune cells secrete cytokines and pro-inflammatory mediators to activate nearby endothelial cells initiating circulating immune cell extravasation into the damaged tissue (Vestweber, 2015). As previously discussed, the influx of neutrophils, activated monocytes, and pro-inflammatory MΦs are central for skeletal muscle repair and remodeling. A key function of neutrophils in promoting cell death is the generation of ROS through NADPH oxygenase-dependent mechanisms (Kolaczkowska and Kubes, 2013). While ROS can be destructive to skeletal muscle in several ways, ROS is an important regulator of skeletal muscle vascular permeability (Korthuis et al., 1985). VEGF has received significant attention for its role in stimulating angiogenesis and promotion of vascular permeability is vital for skeletal muscle repair and remodeling (Arsic et al., 2004). Endothelial cells rely heavily on self VEGF production and autocrine signaling for vascular homeostasis and this autocrine signaling cascade differs from exogenous or paracrine VEGF signaling (Lee et al., 2007). Interestingly, VEGF has been implicated as a regulator of DC differentiation and MΦ polarization (Li et al., 2016b). While monocytes and MCP-1 stimulate the release of VEGF by endothelial cells to increase myofibrillar vascularization during the later stages of repair (Hong et al., 2005), tumor associated macrophages (TAMs) promote the release of VEGF to promote tumor vascularization (Wynn et al., 2013). However, IL-4 inhibits basic Fibroblast Growth Factor (bFGF) induced angiogenesis (Volpert et al., 1998). Therefore, it is vital to understand off-target effects of modulating immune cells and their inflammatory mediators on the endothelium within the skeletal muscle microenvironment.

Endothelial cells have sustained significant attention in tumor cell biology given the importance of tumor vascularization in tumor cell growth and metastasis (Dudley, 2012; Li et al., 2016b). Naturally, treatments targeting endothelial cells and mitigating vascularization has emerged as a promising therapy; however, given the importance of vascular homeostasis in maintaining healthy tissue, the off-target implications of these treatments invoke caution (Morabito et al., 2006). While the effects of cachexia and chemotherapy on the skeletal muscle endothelium or the relationship between immune cells and the skeletal muscle endothelium has not been directly studied, we can glean information from studies examining aging, non-cancer-induced cachexia, and established inflammatory signaling and nutrient availability mechanisms. For instance, COPD patients suffering from cachexia have reduced skeletal muscle capillary density partly caused by deconditioning (Jobin et al., 1998); given that cancer patients experience fatigue and reduced activity, we can expect that cachectic skeletal muscle with cancer has decreased vascularization. Reduced vascularization would diminish skeletal muscle’s regenerative capacity resulting in increased fibrosis, reduced strength, and fatigue (Arsic et al., 2004; Allen et al., 2008; Inaba et al., 2018; Judge et al., 2018; Vanderveen et al., 2018). Additionally, aging processes contributing to frailty has been associated with endothelial dysfunction (Argiles et al., 2016). Inhibition of angiogenesis is a critical target for some chemotherapeutics aimed at preventing vascularization of solid tumors through suppressing VEGF (Zhang et al., 2002; Shih and Lindley, 2006; Ooyama et al., 2008; Bozzetti, 2020). The impact on non-cancerous tissues continues to be unearthed; however, endothelial dysfunction has been demonstrated during chemotherapy driven cardiotoxicity (Brown et al., 2012). Additionally, anti-angiogenic therapies should aim to achieve vascular normalization in order to maintain the delivery and anti-tumor efficacy of chemotherapeutics as opposed to eliminating tumor vascularity completely (Viallard and Larrivee, 2017). Chemotherapy’s effect on skeletal muscle’s endothelium has not been directly investigated. Given the neutrophil’s role in ROS generation, the neutropenia associated with chemotherapy may inhibit the skeletal muscle’s ability to increase vascular permeability and immune cell extravasation. Further work is needed to understand the impact of cancer and its treatments on skeletal muscle’s vascular endothelium.

The nervous and musculoskeletal systems are inextricably linked through the motor unit and denervation, or the loss of the neuromuscular junction (NMJ), results in loss of function and rapid muscle atrophy (Bonaldo and Sandri, 2013). Denervation results in the affected myofibers losing their contractile capacity, which is then followed by a marked reduction in myofibrillar cross sectional area. If the NMJ is not restored, the affected myofibers will become unrecognizable, as they lose their sarcomeric structure and become fibrotic (Carlson, 2014). Similar to other atrophic conditions, MΦs have been identified as contributors to denervation-induced fibrosis (Mochizuki et al., 2005). Interestingly, denervation with cancer cachexia has been suggested in C26 mice (Daou et al., 2020), and neurotoxicity was observed with chemotherapeutic Folfiri (Barreto et al., 2016a); however, gastrointestinal cancer patients with cachexia had no significant loss of NMJs compared to weight stable or health controls (Boehm et al., 2020). Chemotherapeutic DOX disrupted the NMJ in sedentary rats while exercise was able to improve neuromuscular gene and protein expression (Huertas et al., 2020).

BV and EM were employed by company AcePre, LLC.The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.