Muscle wasting is a decline in skeletal muscle mass and function that is associated with aging, obesity, and a spectrum of pathologies including cancer. Cancer-associated wasting not only reduces quality of life, but also directly impacts cancer mortality, chemotherapeutic efficacy, and surgical outcomes. There is an incomplete understanding of the role of tumor-derived factors in muscle wasting and sparse knowledge of how these factors impact in vivo muscle regeneration. Here, we identify several cytokines/chemokines that negatively impact in vitro myogenic differentiation. We show that one of these cytokines, CXCL1, potently antagonizes in vivo muscle regeneration and interferes with in vivo muscle satellite cell homeostasis. Strikingly, CXCL1 triggers a robust and specific neutrophil/M2 macrophage response that likely underlies or exacerbates muscle repair/regeneration defects. Taken together, these data highlight the pleiotropic nature of a novel tumor-derived cytokine and underscore the importance of cytokines in muscle progenitor cell regulation.

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Background: Loss of muscle mass and function are major clinical phenomena 1 affecting most advanced cancer patients. Recent work shows that defects in 2 muscle regeneration contribute to cancer-associated wasting. Among the factors 3 implicated in wasting-associated suppression of muscle regeneration are 4 cytokines that interfere with myogenic signal transduction pathways. Less 5 understood is how other cancer/wasting-associated cues, such as 6 oncometabolites, contribute to muscle dysfunction. This study investigates how 7 the oncometabolite succinate affects myogenesis and muscle regeneration. 8 Methods:We leveraged an established ectopic metabolite treatment strategy to 9 evaluate the ability of intracellular succinate elevation to 1) affect myoblast 10 homeostasis (growth/proliferation, apoptosis), 2) stimulate wasting-associated 11 catabolism, and 3) modulate in vitro myogenesis. In vivo succinate 12 supplementation experiments were utilized to corroborate and extend in vitro 13 observations. Metabolic studies were then performed to investigate the impact of 14 succinate elevation on mitochondria function. 15Results: We found that in vitro succinate elevation in myoblasts interferes with 16 protein homeostasis and myogenic differentiation. Mice orally administered 17 succinate displayed smaller muscle myofiber diameters and exhibited impaired 18 skeletal muscle regeneration when challenged with barium chloride-induced 19 muscle injury. Finally, we found that succinate elevation was associated with 20 functional mitochondria deficits. 21 Conclusions: Overall, this study broadens the repertoire of wasting-associated 22 factors that can directly modulate muscle progenitor cell function and strengthens 23 the hypothesis that metabolic derangements are major contributors to cancer-24 associated muscle wasting. 25 Keywords: Muscle wasting, skeletal muscle, succinate, myogenesis 26 27 Succinate is an oncometabolite best known for its role as a TCA cycle 57 intermediate and central player in mitochondria metabolism and ATP generation. 58 Recently, new roles for succinate have emerged and include immune cell 59 modulation13, HIF-1a stabilization in cancer14, epigenome remodeling via 60 inhibition of alpha-ketoglutarate dependent dioxygenases15, and post-61 translational protein modification (succinylation)16. This expanding repertoire of 62 cellular activities suggests a broader role for succinate in regulating cellular 63 processes such as differentiation, fate decisions, and survival. Interestingly, a 64 recent study reported serum succinate accumulation as a biomarker capable of 65 distinguishing non-wasting, tumor-bearing, and tumor-bearing with weight loss 66 patients17. In the present study, we sought to determine if succinate elevation 67 directly impacts muscle cell function, with a particular emphasis on myogenic 68 differentiation given prior studies linking succinate levels to cell fate 69 decisions18,19. 70Alterations in the balance between muscle breakdown and 71 repair/regeneration underlie cancer-asso...

Background: Cancer-associated muscle wasting (CAW), a symptom of cancer 2 cachexia, is associated with approximately 20% of lung cancer deaths, and 3 remains poorly characterized on a mechanistic level. Current animal models for 4 lung cancer-associated cachexia are limited in that they: 1) primarily employ flank 5 transplantation methods, 2) have short survival times not reflective of the patient 6 condition, and 3) are typically performed in young mice not representative of 7 mean patient age. This study investigates a new model for lung cancer-8 associated cachexia that can address these issues and also implicates muscle 9 regeneration as a contributor to CAW. 10 Methods:We used tail vein injection as a method to introduce tumor cells that 11 seed primarily in the lungs of mice. Body composition of tumor bearing mice was 12 longitudinally tracked using magnetic resonance imaging (MRI). These data were 13 combined with histological and molecular assessments of skeletal muscle to 14 provide a complete analysis of muscle wasting. 15Results: In this new lung CAW model we observed 1) progressive loss in whole 16 body weight, 2) progressive loss of lean and fat mass, 3) a circulating 17 cytokine/inflammatory profile similar to that seen in other models of CAW, 4) 18 histological changes associated with muscle wasting, and 5) molecular changes 19 in muscle that implicate suppression of muscle repair/regeneration. Finally, we 20show that survival can be extended without lessening CAW by titrating injected 21 cell number. 22Conclusions: Overall, this study describes a new model of CAW that could be 23 useful for further studies of lung cancer-associated wasting and accompanying 24 changes in the regenerative capacity of muscle. Additionally, this model 25 addresses many recent concerns with existing models such as 26 immunocompetence, location of tumor, and survival time. 27