James A. Carson

FOLFOX chemotherapy is a common treatment for colorectal cancer, consisting of a combination of the antimetabolite 5-FU, leucovorin, and oxaliplatin. The disruption of muscle cellular signaling caused by 5-FU-based chemotherapies, which leads to fatigue and weakness, remains poorly understood. Our results provide evidence that FOLFOX can directly suppress myotube AMPK signaling, protein synthesis, and autophagy flux. Importantly, the effects of FOLFOX and the resulting disruptions to muscle protein turnover are long-lasting and are not easily reversible.

Our adult population's metabolic health and overall functional capacity are directly linked to skeletal muscle mass maintenance (1-4). Furthermore, skeletal muscle loss and metabolic dysfunction that can occur in many disease conditions can impact patient survival, health, and quality of life, key outcomes for successful treatment (2,3). We know that muscle mass and metabolic properties are related to a variety of factors, including muscle loading and activity levels, nutrition, and hormones (5). Consequently, maintaining muscle mass and regrowing it after atrophy have become a critical goal for many adults due to periods of forced immobility, sedentary behavior, and chronic disease. There is a need for new strategies and approaches to improve muscle accretion in individuals with low muscle mass, as well as for novel therapeutic targets to enhance muscle mass recovery from atrophy (6). The emerging view of muscle mass regulation across many conditions involves the integration of multiple stimuli, synthesized by intracellular pathways and processes, into a muscle anabolic or catabolic response that results in muscle accretion or loss (7). Furthermore, healthy skeletal muscle is highly responsive to systemic and microenvironmental factors. Hormonal and growth factor stimuli, including testosterone, IGF-1, and Growth Hormone, have established roles in regulating muscle growth. While less acknowledged, estrogen is also a potent regulator of muscle mass and metabolism (4,8). Interestingly, while hypogonadism is a hallmark of many conditions and diseases that induce muscle wasting (1,4), it has received much less attention from the scientific community compared to factors such as chronic inflammation or insulin resistance. An improved understanding of the contribution of hypogonadism in males and females to muscle wasting in many conditions has critical clinical implications for human health. While there has been significant advancement in understanding the molecular drivers of hormone-induced muscle hypertrophy, the repercussions for muscle mass loss and recovery in many conditions are multifactorial and more challenging to target. The regulation of muscle mass by hormones and growth factors remains an active area of inquiry. The muscle environment can also involve crosstalk between tissues, such as bone, and target many muscle cell types, including myofibers, satellite cells, immune cells, endothelial cells, and fibroblasts. The presentation will highlight the importance of gonadal function for maintaining muscle mass in conditions such as cancer. Specific examples will be provided for the critical role of the ovary in skeletal muscle regulation of mass and metabolism in the female, which can be disrupted by several factors, including cancer and treatment.

Purpose of review: The purpose of this review is to highlight recently published research that can provide insight into how either sex or chemotherapeutics can impact cancer regulation of muscle anabolic resistance. Critical knowledge gaps are emphasized that are linked to cancer and treatment disruptions to muscle anabolic signaling. We speculate and propose a rationale for estrogen's protective effect against cancer-induced muscle anabolic resistance in females. Furthermore, there is growing evidence that many cancer treatments have the potential to exacerbate muscle anabolic resistance in both males and females. We present current evidence and speculate on how nutritional interventions could serve as key modulators of cancer-induced anabolic resistance in these conditions. Recent findings: Recently published studies have reinforced that sex impacts the regulation of cancer cachexia in several established preclinical models, with males often developing more severe cachexia when compared to females. Importantly, recent research has established these sex differences at the transcriptomic level. Recent research has also strengthened the link between hypogonadism as a driver of cancer cachexia in preclinical models. Furthermore, chemotherapy has the potential to exacerbate muscle anabolic resistance. Summary: There is a growing body of literature that provides a strong rationale for further investigation into the impact of sex and chemotherapy on the cancer regulation of muscle anabolic resistance.

Electrically evoked muscle contractions conducted every other day after muscle injury caused additional damage and slowed recovery of muscle regeneration; however, mitochondria transplantation attenuated the negative regenerative effects of rehabilitative contractions on muscle fiber regeneration. This suggests that optimizing mitochondrially regulated repair may improve muscle regeneration. Furthermore, injured muscles treated by mitochondrial transplantation had lower collagen content/fibrosis than those treated with PBS after injury. Mitochondrial transplantation blunts fibrosis and improves muscle fiber repair after injury.

The present study demonstrates that in colon tumor-bearing mice, the administration of FOLFOX chemotherapy alters plasma inflammatory cytokines’ relationship to tumor mass, body composition, and physical function. Furthermore, sex influences these responses. These findings have implications for mechanistically understanding sex-specific muscle wasting and metabolic complications experienced by patients with colorectal cancer undergoing chemotherapy treatment.

Background: Cancer promotes muscle wasting through an imbalance in the tightly regulated protein synthesis and degradation processes. An array of intracellular signalling pathways, including mTORC1 and AMPK, regulate protein synthesis, and these pathways are responsive to the muscle's microenvironment and systemic stimuli. Although feeding and fasting are established systemic regulators of muscle mTORC1 and protein synthesis, the cancer environment's impact on these responses during cachexia development is poorly understood. Although the IL‐6 cytokine family has been widely investigated as a driver of cachexia with several cancers, how this signalling regulates muscle responses to feeding and fasting requires further study. We investigated if the cancer environment alters the feeding and fasting regulation of skeletal muscle protein synthesis and if the IL‐6 family of cytokines signalling through muscle glycoprotein 130 could regulate this response. Methods: Male C57BL/6J mice were subcutaneously injected with 1 × 10 ⁶ LLC cells or PBS. Mice were euthanized 25–30 days post‐injection after a 12‐h dark cycle fast, followed by access to food pellets for 1 h (fed) or immediately sacrificed. To determine AMPK and gp13's regulation of protein synthesis and anabolic signalling, we injected tamoxifen‐inducible skeletal muscle AMPKa ¹ a ² or gp130 knockout and floxed control mice with LLC cells or PBS. The gastrocnemius muscle was analysed for protein expression. Results: Feeding increased p‐rpS6 and protein synthesis in PBS (2.2‐ and 0.4‐fold, p < 0.001) and LLC mice (1.7‐ and 0.9‐fold, p < 0.001), but overall, LLC significantly reduced p‐rpS6 and protein synthesis. Feeding only increased p‐AKT in PBS mice (1.5‐fold, p < 0.001). In vitro LLC‐conditioned media did not inhibit the insulin induction of myotube p‐AKT ( p < 0.001) and p‐rpS6 ( p < 0.001). Muscle gp130 loss reduced the fasting p‐AMPK induction in LLC mice but did not alter suppression of p‐AKT and p‐rpS6 and protein synthesis. Muscle AMPK loss increased p‐rpS6 (2.1‐fold, p < 0.001) and protein synthesis (0.7‐fold, p < 0.001) in PBS mice but did not restore LLC‐suppressed protein synthesis. Conclusions: Our study provides novel insight into muscle responsiveness to feeding and fasting in a cancer environment. We find the acute anabolic response to feeding is maintained during LLC‐induced cachexia, whereas the fasting catabolic response is exacerbated. Muscle‐specific gp130 loss prevented disrupted fasting AMPK activation but not protein synthesis. There is a need to understand the aberrant upstream and downstream regulation of muscle AMPK activity that is disrupted with cancer and leads to aberrant protein turnover regulation.

Skeletal muscle’s metabolic and mechanical functions make it critical for maintaining human health, physical function, and quality of life in adults. The impact of skeletal muscle mass and the metabolic quality of muscle tissue becomes even more critical with advancing age and in patients with chronic diseases. To this end, cachexia is the involuntary loss of body weight, including muscle and fat loss, accompanying an underlying disease or condition. Cancer-induced cachexia occurs across many types of cancer and contributes to increased patient mortality, morbidity, and treatment toxicities, negatively impacting survival. Furthermore, there are currently no approved pharmacological treatments and limited evidence-based therapeutic options to prevent muscle loss or promote muscle recovery in cancer patients. While the systemic effects of cancer and subsequent treatment continue to be examined as drivers of overall wasting, the impact of skeletal muscle mass and metabolic quality in the cancer patient remains a critical area of investigation. A vital knowledge gap exists in understanding how maintaining muscle function and metabolic properties improves cancer patients’ survival. The chapter explores the current understanding of how cancer and subsequent treatment impact skeletal muscle mass, function, and metabolic quality. To this end, the current understanding of systemic mediators and metabolic crosstalk between tissues that promote cancer-induced wasting is explored. Additional factors related to sex, physical activity level, chemotherapy-specific effects, and cancer heterogeneity are discussed concerning their impact on cancer-induced muscle wasting.

Human Interleukin-6 (hIL-6) is a pro inflammatory cytokine that binds to its receptor, IL-6Rα followed by binding to gp130 and subsequent dimerization to form a hexamer signaling complex. As a critical inflammation mediator, hIL-6 is associated with a diverse range of diseases and monoclonal antibodies in clinical use that either target IL-6Rα or hIL-6 to inhibit signaling. Here, we perform high-throughput structure-based computational screening using ensemble docking for small-molecule antagonists for which the target conformations were taken from 600 ns long molecular dynamics simulations of the apo protein. Prior knowledge of the contact sites from binary complex studies and experimental work was incorporated into the docking studies. The top 20 scoring ligands from the in silico studies after post analysis were subjected to in vitro functional assays. Among these compounds, the ligand with the second-highest calculated binding affinity experimentally showed an ~84% inhibitory effect on IL6-induced STAT3 reporter activity at 10 μM concentration. This finding may pave the way for designing small-molecule inhibitors of hIL-6 of therapeutic significance.

We sought to advance our understanding of skeletal muscle lipid metabolism and dynamics in cancer cachexia. Cachexia increased the number and size of intramyocellular lipid droplets (LDs). Furthermore, decreases in LD-mitochondrial touch, contact length, and relative contact along with increased LD shape complexity with decreases in circularity and roundness. Dysregulation in lipid metabolism and LD-associated proteins was also documented. Collectively, we show that myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in cancer cachexia.