Chronic inflammation is a hallmark of cancer cachexia in both patients and preclinical models. Cachexia is prevalent in roughly 80% of cancer patients and accounts for up to 20% of all cancer-related deaths. Proinflammatory cytokines IL-6, TNF-α, and TGF-β have been widely examined for their regulation of cancer cachexia. An established characteristic of cachectic skeletal muscle is a disrupted capacity for oxidative metabolism, which is thought to contribute to cancer patient fatigue, diminished metabolic function, and muscle mass loss. This review's primary objective is to highlight emerging evidence linking cancer-induced inflammation to the dysfunctional regulation of mitochondrial dynamics, mitophagy, and biogenesis in cachectic muscle. The potential for either muscle inactivity or exercise to alter mitochondrial dysfunction during cancer cachexia will also be discussed.

While skeletal muscle mass is an established primary outcome related to understanding cancer cachexia mechanisms, considerable gaps exist in our understanding of muscle biochemical and functional properties that have recognized roles in systemic health. Skeletal muscle quality is a classification beyond mass, and is aligned with muscle's metabolic capacity and substrate utilization flexibility. This supplies an additional role for the mitochondria in cancer-induced muscle wasting. While the historical assessment of mitochondria content and function during cancer-induced muscle loss was closely aligned with energy flux and wasting susceptibility, this understanding has expanded to link mitochondria dysfunction to cellular processes regulating myofiber wasting. The primary objective of this article is to highlight muscle mitochondria and oxidative metabolism as a biological target of cancer cachexia and also as a cellular regulator of cancer-induced muscle wasting. Initially, we examine the role of muscle metabolic phenotype and mitochondria content in cancer-induced wasting susceptibility. We then assess the evidence for cancer-induced regulation of skeletal muscle mitochondrial biogenesis, dynamics, mitophagy, and oxidative stress. In addition, we discuss environments associated with cancer cachexia that can impact the regulation of skeletal muscle oxidative metabolism. The article also examines the role of cytokine-mediated regulation of mitochondria function regulation, followed by the potential role of cancer-induced hypogonadism. Lastly, a role for decreased muscle use in cancer-induced mitochondrial dysfunction is reviewed.

While cancer-induced skeletal muscle wasting has been widely investigated, the drivers of cancer-induced muscle functional decrements are only beginning to be understood. Decreased muscle function impacts cancer patient quality of life and health status, and several potential therapeutics have failed in clinical trials due to a lack of functional improvement. Furthermore, systemic inflammation and intrinsic inflammatory signaling's role in the cachectic disruption of muscle function requires further investigation. We examined skeletal muscle functional properties during cancer cachexia and determined their relationship to systemic and intrinsic cachexia indices. Male Apc (MIN) mice were stratified by percent body weight loss into weight stable (WS; <5% loss) or cachectic (CX; >5% loss). Age-matched C57BL/6 littermates served as controls. Tibialis anterior (TA) twitch properties, tetanic force, and fatigability were examined in situ. TA protein and mRNA expression were examined in the nonstimulated leg. CX decreased muscle mass, tetanic force (P), and specific tetanic force (P). Whole body and muscle fatigability were increased in WS and CX. CX had slower contraction rates, +dP/d t and -dP/d t, which were inversely associated with muscle signal transducer and activator of transcription 3 ( STAT3) and p65 activation. STAT3 and p65 activation were also inversely associated with P. However, STAT3 was not related to P or fatigue. Muscle suppressor of cytokine signaling 3 mRNA expression was negatively associated with TA weight, P, and P but not fatigue. Our study demonstrates that multiple functional deficits that occur with cancer cachexia are associated with increased muscle inflammatory signaling. Notably, muscle fatigability is increased in the MIN mouse before cachexia development. NEW & NOTEWORTHY Recent studies have identified decrements in skeletal muscle function during cachexia. We have extended these studies by directly relating decrements in muscle function to established cachexia indices. Our results demonstrate that a slow-fatigable contractile phenotype is developed during the progression of cachexia that coincides with increased muscle inflammatory signaling. Furthermore, regression analysis identified predictors of cancer-induced muscle dysfunction. Last, we report the novel finding that whole body and muscle fatigability were increased before cachexia development.

BackgroundSkeletal muscle responds to eccentric contractions (ECC) with an anabolic response that involves the induction of protein synthesis through the mechanistic target of rapamycin complex 1. While we have reported that repeated ECC bouts after cachexia initiation attenuated muscle mass loss and inflammatory signalling, cachectic muscle's capacity to induce protein synthesis in response to ECC has not been determined. Therefore, we examined cachectic muscle's ability to induce mechano‐sensitive pathways and protein synthesis in response to an anabolic stimulus involving ECC and determined the role of muscle signal transducer and activator of transcription 3 (STAT3)/nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB) signalling on ECC‐induced anabolic signalling.MethodsMechano‐sensitive pathways and anabolic signalling were examined immediately post or 3 h after a single ECC bout in cachectic male Apc Min/+ mice (n = 17; 16 ± 1% body weight loss). Muscle STAT3/NFκB regulation of basal and ECC‐induced anabolic signalling was also examined in an additional cohort of Apc Min/+ mice (n = 10; 16 ± 1% body weight loss) that received pyrrolidine dithiocarbamate 24 h prior to a single ECC bout. In all experiments, the left tibialis anterior performed ECC while the right tibialis anterior served as intra‐animal control. Data were analysed by Student's t‐test or two‐way repeated measures analysis of variance with Student‐Newman‐Keuls post‐hoc when appropriate. The accepted level of significance was set at P < 0.05 for all analysis.Results Apc Min/+ mice exhibited a cachectic muscle signature demonstrated by perturbed proteostasis (Ribosomal Protein S6 (RPS6), P70S6K, Atrogin‐1, and Muscle RING‐finger protein‐1 (MuRF1)), metabolic (adenosine monophosphate‐activated protein kinase, Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α), and Cytochrome c oxidase subunit IV (COXIV)), and inflammatory (STAT3, NFκB, extracellular signal‐regulated kinases 1 and 2, and P38) signalling pathway regulation. Nonetheless, mechano‐sensitive signalling pathways (P38, extracellular signal‐regulated kinases 1 and 2, and Protein kinase B (AKT)) were activated immediately post‐ECC irrespective of cachexia. While cachexia did not attenuate ECC‐induced P70S6K activation, the protein synthesis induction remained suppressed compared with healthy controls. However, muscle STAT3/NFκB inhibition increased basal and ECC‐induced protein synthesis in cachectic Apc Min/+ mice.ConclusionsThese studies demonstrate that mechano‐sensitive signalling is maintained in cachectic skeletal muscle, but chronic STAT3/NFκB signalling serves to attenuate basal and ECC‐induced protein synthesis.

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Skeletal muscle has the dynamic capability to modulate protein turnover in response to anabolic stimuli, such as feeding and contraction. We propose that anabolic resistance, the suppressed ability to induce protein synthesis, is central to cancer-induced muscle wasting. Furthermore, we propose that resistance exercise training has the potential to attenuate or treat cancer-induced anabolic resistance through improvements in oxidative metabolism.

5 fluorouracil (5FU) has been a first-choice chemotherapy drug for several cancer types (e.g., colon, breast, head, and neck); however, its efficacy is diminished by patient acquired resistance and pervasive side effects. Leukopenia is a hallmark of 5FU; however, the impact of 5FU-induced leukopenia on healthy tissue is only becoming unearthed. Recently, skeletal muscle has been shown to be impacted by 5FU in clinical and preclinical settings and weakness and fatigue remain among the most consistent complaints in cancer patients undergoing chemotherapy. Monocytes, or more specifically macrophages, are the predominate immune cell in skeletal muscle which regulate turnover and homeostasis through removal of damaged or old materials as well as coordinate skeletal muscle repair and remodeling. Whether 5FU-induced leukopenia extends beyond circulation to impact resident and infiltrating skeletal muscle immune cells has not been examined. The purpose of the study was to examine the acute effects of 5FU on resident and infiltrating skeletal muscle monocytes and inflammatory mediators. Male C57BL/6 mice were given a physiologically translatable dose (35 mg/kg) of 5FU, or PBS, i.p. once daily for 5 days to recapitulate 1 dosing cycle. Our results demonstrate that 5FU reduced circulating leukocytes, erythrocytes, and thrombocytes while inducing significant body weight loss (&gt;5%). Flow cytometry analysis of the skeletal muscle indicated a reduction in total CD45+ immune cells with a corresponding decrease in total CD45+CD11b+ monocytes. There was a strong relationship between circulating leukocytes and skeletal muscle CD45+ immune cells. Skeletal muscle Ly6cHigh activated monocytes and M1-like macrophages were reduced with 5FU treatment while total M2-like CD206+CD11c- macrophages were unchanged. Interestingly, 5FU reduced bone marrow CD45+ immune cells and CD45+CD11b+ monocytes. Our results demonstrate that 5FU induced body weight loss and decreased skeletal muscle CD45+ immune cells in association with a reduction in infiltrating Ly6cHigh monocytes. Interestingly, the loss of skeletal muscle immune cells occurred with bone marrow cell cycle arrest. Together our results highlight that skeletal muscle is sensitive to 5FU’s off-target effects which disrupts both circulating and skeletal muscle immune cells.

New Findings What is the central question of this study?Interleukin‐6 has been associated with muscle mass and metabolism in both physiological and pathological conditions. A causal role for interleukin‐6 in the induction of fatigue and disruption of mitochondrial function has not been determined. What is the main finding and its importance?We demonstrate that chronically elevated interleukin‐6 increased skeletal muscle fatigability and disrupted mitochondrial content and function independent of changes in fibre type and mass. Abstract Interleukin‐6 (IL‐6) can initiate intracellular signalling in skeletal muscle by binding to the IL‐6‐receptor and interacting with the transmembrane gp130 protein. Circulating IL‐6 has established effects on skeletal muscle mass and metabolism in both physiological and pathological conditions. However, the effects of circulating IL‐6 on skeletal muscle function are not well understood. The purpose of this study was to determine whether chronically elevated systemic IL‐6 was sufficient to disrupt skeletal muscle force, fatigue and mitochondrial function. Additionally, we examined the role of muscle gp130 signalling during overexpression of IL‐6. Systemic IL‐6 overexpression for 2 weeks was achieved by electroporation of an IL‐6 overexpression plasmid or empty vector into the quadriceps of either C57BL/6 (WT) or skeletal muscle gp130 knockout (KO) male mice. Tibialis anterior muscle in situ functional properties and mitochondrial respiration were determined. Interleukin‐6 accelerated in situ skeletal muscle fatigue in the WT, with a 18.5% reduction in force within 90 s of repeated submaximal contractions and a 7% reduction in maximal tetanic force after 5 min. There was no difference between fatigue in the KO and KO+IL‐6. Interleukin‐6 reduced WT muscle mitochondrial respiratory control ratio by 36% and cytochrome c oxidase activity by 42%. Interleukin‐6 had no effect on either KO respiratory control ratio or cytochrome c oxidase activity. Interleukin‐6 also had no effect on body weight, muscle mass or tetanic force in either genotype. These results provide evidence that 2 weeks of elevated systemic IL‐6 is sufficient to increase skeletal muscle fatigability and decrease muscle mitochondrial content and function, and these effects require muscle gp130 signalling.