Insulin-like growth factor-1 (IGF-1) is a key growth factor that regulates both anabolic and catabolic pathways in skeletal muscle. IGF-1 increases skeletal muscle protein synthesis via PI3K/Akt/mTOR and PI3K/Akt/GSK3β pathways. PI3K/Akt can also inhibit FoxOs and suppress transcription of E3 ubiquitin ligases that regulate ubiquitin proteasome system (UPS)-mediated protein degradation. Autophagy is likely inhibited by IGF-1 via mTOR and FoxO signaling, although the contribution of autophagy regulation in IGF-1-mediated inhibition of skeletal muscle atrophy remains to be determined. Evidence has suggested that IGF-1/Akt can inhibit muscle atrophy-inducing cytokine and myostatin signaling via inhibition of the NF-κΒ and Smad pathways, respectively. Several miRNAs have been found to regulate IGF-1 signaling in skeletal muscle, and these miRs are likely regulated in different pathological conditions and contribute to the development of muscle atrophy. IGF-1 also potentiates skeletal muscle regeneration via activation of skeletal muscle stem (satellite) cells, which may contribute to muscle hypertrophy and/or inhibit atrophy. Importantly, IGF-1 levels and IGF-1R downstream signaling are suppressed in many chronic disease conditions and likely result in muscle atrophy via the combined effects of altered protein synthesis, UPS activity, autophagy, and muscle regeneration.

Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy

Cancer cachexia (CC) is a multifactorial syndrome in patients with advanced cancer characterized by weight loss via skeletal-muscle and adipose-tissue atrophy, catabolic activity, and systemic inflammation. CC is correlated with functional impairment, reduced therapeutic responsiveness, and poor prognosis, and is a major cause of death in cancer patients. In colorectal cancer (CRC), cachexia affects around 50-61% of patients, but remains overlooked, understudied, and uncured. The mechanisms driving CC are not fully understood but are related, at least in part, to the local and systemic immune response to the tumor. Accumulating evidence demonstrates a significant role of tumor microenvironment (TME) cells (e.g., macrophages, neutrophils, and fibroblasts) in both cancer progression and tumor-induced cachexia, through the production of multiple procachectic factors. The most important role in CRC-associated cachexia is played by pro-inflammatory cytokines, including the tumor necrosis factor α (TNFα), originally known as cachectin, Interleukin (IL)-1, IL-6, and certain chemokines (e.g., IL-8). Heterogeneous CRC cells themselves also produce numerous cytokines (including chemokines), as well as novel factors called "cachexokines". The tumor microenvironment (TME) contributes to systemic inflammation and increased oxidative stress and fibrosis. This review summarizes the current knowledge on the role of TME cellular components in CRC-associated cachexia, as well as discusses the potential role of selected mediators secreted by colorectal cancer cells in cooperation with tumor-associated immune and non-immune cells of tumor microenvironment in inducing or potentiating cancer cachexia. This knowledge serves to aid the understanding of the mechanisms of this process, as well as prevent its consequences.

https://www.mdpi.com/1422-0067/22/4/1565/pdf

The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia.

Diverse inflammatory diseases, infections and malignancies are associated with wasting syndromes. In many of these conditions, the standards for diagnosis and treatment are lacking due to our limited understanding of the causative molecular mechanisms. Here, we discuss the complex immunological context of cachexia, a systemic catabolic syndrome that depletes both fat and muscle mass with profound consequences for patient prognosis. We highlight the main cytokine and immune cell-driven pathways that have been linked to weight loss and tissue wasting in the context of cancer-associated and infection-associated cachexia. Moreover, we discuss the potential immunometabolic consequences of cachexia on the basis of newly identified pathways and explore the multilayered area of immunometabolic crosstalk both upstream and downstream of tissue catabolism. Collectively, this Review highlights the intricate relationship of the immune system with cachexia in the context of malignant and infectious diseases.

/pdf/the-interplay-of-immunology-and-cachexia-in-infection-and-1w9licacbj.pdf

The interplay of immunology and cachexia in infection and cancer.

Cancer cachexia is a complex multi-organ catabolic syndrome that reduces mobility, increases fatigue, decreases the efficiency of therapeutic strategies, diminishes the quality of life, and increases the mortality of cancer patients. This review provides an exhaustive and comprehensive analysis of cancer cachexia-related phenotypic changes in skeletal muscle at both the cellular and subcellular levels in human cancer patients, as well as in animal models of cancer cachexia. Cancer cachexia is characterized by a major decrease in skeletal muscle mass in human and animals that depends on the severity of the disease/model and the localization of the tumour. It affects both type 1 and type 2 muscle fibres, even if some animal studies suggest that type 2 muscle fibres would be more prone to atrophy. Animal studies indicate an impairment in mitochondrial oxidative metabolism resulting from a decrease in mitochondrial content, an alteration in mitochondria morphology, and a reduction in mitochondrial metabolic fluxes. Immuno-histological analyses in human and animal models also suggest that a faulty mechanism of skeletal muscle repair would contribute to muscle mass loss. An increase in collagen deposit, an accumulation of fat depot outside and inside the muscle fibre, and a disrupted contractile machinery structure are also phenotypic features that have been consistently reported in cachectic skeletal muscle. Muscle function is also profoundly altered during cancer cachexia with a strong reduction in skeletal muscle force. Even though the loss of skeletal muscle mass largely contributes to the loss of muscle function, other factors such as muscle-nerve interaction and calcium handling are probably involved in the decrease in muscle force. Longitudinal analyses of skeletal muscle mass by imaging technics and skeletal muscle force in cancer patients, but also in animal models of cancer cachexia, are necessary to determine the respective kinetics and functional involvements of these factors. Our analysis also emphasizes that measuring skeletal muscle force through standardized tests could provide a simple and robust mean to early diagnose cachexia in cancer patients. That would be of great benefit to cancer patient's quality of life and health care systems.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcsm.12678

Phenotypic features of cancer cachexia-related loss of skeletal muscle mass and function: lessons from human and animal studies.

Significance: The management of cancer patients is frequently complicated by the occurrence of a complex syndrome known as cachexia. It is mainly characterized by muscle wasting, a condition that a...

The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?

https://iris.unito.it/bitstream/2318/1711255/1/manuscript%20revised%20unmarked.pdf

Paula Martinez-Cristobal

Papers

Autophagy Exacerbates Muscle Wasting in Cancer Cachexia and Impairs Mitochondrial Function