Muscle Atrophy In Cachexia Research Articles

The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia.

Simple SummaryThe mechanism of cancer cachexia is linked to a variety of factors, and inflammatory factors are thought to play a key role. We summarize the main roles of LIF in the development of cancer cachexia, including promoting fat loss, inducing skeletal muscle atrophy and causing anorexia nervosa. The main aim of this review is to increase the understanding of the effects of LIF in cachexia and to provide new insights into the treatment of cancer cachexia.Cachexia is a chronic metabolic syndrome that is characterized by sustained weight and muscle mass loss and anorexia. Cachexia can be secondary to a variety of diseases and affects the prognosis of patients significantly. The increase in inflammatory cytokines in plasma is deeply related to the occurrence of cachexia. As a member of the IL-6 cytokine family, leukemia inhibitory factor (LIF) exerts multiple biological functions. LIF is over-expressed in the cancer cells and stromal cells of various tumors, promoting the malignant development of tumors via the autocrine and paracrine systems. Intriguingly, increasing studies have confirmed that LIF contributes to the progression of cachexia, especially in patients with metastatic tumors. This review combines all of the evidence to summarize the mechanism of LIF-induced cachexia from the following four aspects: (i) LIF and cancer-associated cachexia, (ii) LIF and alterations of adipose tissue in cachexia, (iii) LIF and anorexia nervosa in cachexia, and (iv) LIF and muscle atrophy in cachexia. Considering the complex mechanisms in cachexia, we also focus on the interactions between LIF and other key cytokines in cachexia and existing therapeutics targeting LIF.

Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia

BackgroundEighty per cent of United States advanced cancer patients faces a worsened prognosis due to cancer‐associated cachexia. Inflammation is one driver of muscle atrophy in cachexia, and skeletal muscle‐resident immune cells could be a source of inflammation. This study explores the efficacy of cancer activated skeletal muscle‐resident mast cells as a biomarker and mediator of cachexia.MethodsIndividual gene markers for immune cells were assessed in a publicly available colon carcinoma cohort of normal (n = 3), moderate cachexia (n = 3), and severe cachexia (n = 4) mice. Lewis lung carcinoma (LL/2) cells induced cachexia in C57BL/6 mice, and a combination of toluidine blue staining, immunofluorescence, quantitative polymerase chain reaction, and western blots measured innate immune cell expression in hind limb muscles. In vitro measurements included C2C12 myotube diameter before and after treatment with media from primary murine mast cells activated with LL/2 conditioned media. To assess translational potential in human samples, innate immune cell signatures were assessed for correlation with skeletal muscle atrophy and apoptosis, dietary excess, and cachexia signatures in normal skeletal muscle tissue. Gene set enrichment analysis was performed with innate immune cell signatures in publicly available cohorts for upper gastrointestinal (GI) cancer and pancreatic ductal adenocarcinoma (PDAC) patients (accession: GSE34111 and GSE130563, respectively).ResultsIndividual innate immunity genes (TPSAB1 and CD68) showed significant increases in severe cachexia (weight loss > 15%) mice in a C26 cohort (GSE24112). Induction of cachexia in C57BL/6 mice with LL/2 subcutaneous injection significantly increased the number of activated skeletal muscle‐resident degranulating mast cells. Murine mast cells activated with LL/2 conditioned media decreased C2C12 myotube diameter (P ≤ 0.05). Normal human skeletal muscle showed significant positive correlations between innate immune cell signatures and muscle apoptosis and atrophy, dietary excess, and cachexia signatures. The mast cell signature was up‐regulated (positive normalized enrichment score and false discovery rate ≤ 0.1) in upper GI cachectic patients (n = 12) compared with control (n = 6), as well as in cachectic PDAC patients (n = 17) compared with control patients (n = 16).ConclusionsActivated skeletal muscle‐resident mast cells are enriched in cachectic muscles, suggesting skeletal‐muscle resident mast cells may serve as a biomarker and mediator for cachexia development to improve patient diagnosis and prognosis.

Regulation of Skeletal Muscle Atrophy in Cachexia by MicroRNAs and Long Non-coding RNAs.

Skeletal muscle atrophy is a common complication of cachexia, characterized by progressive bodyweight loss and decreased muscle strength, and it significantly increases the risks of morbidity and mortality in the population with atrophy. Numerous complications associated with decreased muscle function can activate catabolism, reduce anabolism, and impair muscle regeneration, leading to muscle wasting. microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), types of non-coding RNAs, are important for regulation of skeletal muscle development. Few studies have specifically identified the roles of miRNAs and lncRNAs in cellular or animal models of muscular atrophy during cachexia, and the pathogenesis of skeletal muscle wasting in cachexia is not entirely understood. To develop potential approaches to improve skeletal muscle mass, strength, and function, a more comprehensive understanding of the known key pathophysiological processes leading to muscular atrophy is needed. In this review, we summarize the known miRNAs, lncRNAs, and corresponding signaling pathways involved in regulating skeletal muscle atrophy in cachexia and other diseases. A comprehensive understanding of the functions and mechanisms of miRNAs and lncRNAs during skeletal muscle wasting in cachexia and other diseases will, therefore, promote therapeutic treatments for muscle atrophy.

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation, which is seen in as many as 80% of patients with advanced malignancy. It accounts for an estimated 20-30% of all cancer-related deaths. The mechanism by which cancer induces skeletal muscle atrophy in cachexia involves tumor-derived cytokines, including TNF?, IL-1, and IL-6. Upon interaction with their unique receptors on skeletal muscle, these cytokines activate NF-kappaB, a transcription factor crucial for atrophy related sarcomere proteolysis to occur. The significance of NF-?B is highlighted in studies demonstrating that genetic inhibition of NF-?B ameliorates cancer-induced muscle loss in vivo. In the present study, we evaluate a selective NF-kappaB inhibitor (NBD peptide) which targets the IkappaB complex to prevent cancer-induced skeletal muscle atrophy in an established mouse model (C26 adenocarcinoma). We identified for the first time that NBD peptide can directly inhibit tumor-induced NFkappaB activation in skeletal muscle, resulting in a decrease loss of lean muscle. We also identified that NBD peptide reduces the expression of the tumor induced ubiquitin ligases MuRF-1 and MAFbx/Atrogin-1 necessary for atrophy. These findings highlight that NBD peptide may be a potential selective therapeutic agent for the treatment of cancer cachexia.

Muscle atrophy in cachexia: can dietary protein tip the balance?

To review the efficacy of dietary protein supplementation in attenuating muscle atrophy in cachexia. Only very few recent randomized controlled trials have studied the effects of protein supplementation in clinical cachexia. It appears that supplementation of dietary protein (>1.5 g/kg per day) alone or in combination with other anabolic stimuli such as exercise training maintains or even improves muscle mass, but results on muscle function are controversial and no clinical studies have yet directly linked alterations in cellular signaling or metabolic signatures of protein intake-induced muscle anabolism to muscle weight gain. To elucidate the role of dietary protein supplementation in attenuating muscle atrophy in cachectic patients, randomized clinical trials are needed in adequately phenotyped patients using sensitive measures of muscle mass and function.

Role of the ubiquitin-proteasome pathway in muscle atrophy in cachexia

Increased ubiquitin-proteasome-dependent proteolysis is a major determinant of muscle wasting in numerous catabolic states, including cachexia. We discuss the implication of both mechanistic and clinical recent observations for preventing or attenuating the loss of muscle proteins. The ubiquitin-proteasome system (UPS) is the major proteolytic machinery systematically activated in cachexia and only proteasome inhibitors prevent increased proteolysis. The UPS has been recently demonstrated to degrade myosin heavy chain (i.e. a major contractile protein) and telethonin that plays a role in sarcomere integrity. The UPS is activated at the ubiquitination/deubiquitination and proteasome activity levels. The precise complex and interdependent signalling pathways and transcription factors (i.e. the FoxO family) responsible for the activation of the UPS are in part identified. Recent studies have also shown that FoxO3 activates not only the UPS, but also the transcription of autophagy-related genes. The exact role of the different muscle proteolytic systems and their respective substrates are still largely unknown. However, current studies in animal models of cachexia already identified new pharmacological approaches that could be useful to block or partially prevent muscle wasting in cachectic patients.