Creatine supplementation in Walker-256 tumor-bearing rats prevents skeletal muscle atrophy by attenuating systemic inflammation and protein degradation signaling

Cella, Paola S; Marinello, Poliana Camila; Borges, Fernando H.; Ribeiro, Diogo Farias; Chimin, Patrícia; Testa, Mayra T. J.; Guirro, Philippe B.; Duarte, José Alberto; Cecchini, Rúbens; Guarnier, Flávia Alessandra; Deminice, Rafael

doi:10.1007/s00394-019-01933-6

Cited by 37 publications

(25 citation statements)

References 49 publications

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“…Inflammation is known to be related to skeletal muscle atrophy in critically ill patients (7,23,35). Our previous report has also indicated that inflammation plays a role in skeletal muscle atrophy induced by denervation (2).…”

Section: Activation Of Il-6/jak/stat3 Signaling Pathway In Denervated Skeletal Muscle Atrophymentioning

confidence: 94%

Inhibition of IL-6/JAK/STAT3 pathway rescues denervation-induced skeletal muscle atrophy

Huang¹,

Zhong²,

Zhu³

et al. 2020

Ann Transl Med

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Background: The molecular mechanisms underlying denervated skeletal muscle atrophy with concomitant muscle mass loss have not been fully elucidated. Therefore, this study aimed to attain a deeper understanding of the molecular mechanisms underlying denervated skeletal muscle atrophy as a critical step to developing targeted therapy and retarding the concomitant loss of skeletal muscle mass. Methods:We employed microarray analysis to reveal the potential molecular mechanisms underlying denervated skeletal muscle atrophy. We used in vitro and in vivo atrophy models to explore the roles of the interleukin 6 (IL-6), Janus kinase (JAK), and signal transducers and activators of transcription 3 (STAT3) in muscle atrophy.Results: In this study, microarray analysis of the differentially expressed genes demonstrated that inflammation-related cytokines were markedly triggered and IL-6/JAK/STAT3 signaling pathway was strongly activated during denervated skeletal muscle atrophy. The high level of IL-6 enhanced C2C12 myotube atrophy through the activation of JAK/STAT3, while inhibiting JAK/STAT3 pathway by ruxolitinib (a JAK1/2 inhibitor) or C188-9 (a STAT3 inhibitor) significantly attenuated C2C12 myotube atrophy induced by IL-6. Pharmacological blocking of IL-6 by tocilizumab (antibody against IL-6 receptor) and pharmacological/genetic inhibition of JAK/STAT3 pathway by ruxolitinib/C188-9 (JAK/STAT3 inhibitor) and STAT3 short hairpin RNA (shRNA) lentivirus in tibialis anterior muscles could suppress muscle atrophy and inhibit mitophagy, and was accompanied by the decreased expression of atrophic genes (MuRF1 and MAFbx) and autophagy-related genes (PINK1, BNIP3, Beclin 1, ATG7, and LC3B).Conclusions: Taken together, the results suggest that IL-6/JAK/STAT3 pathway may be a principal mediator in denervated skeletal muscle atrophy, meaning targeted therapy against IL-6/JAK/STAT3 pathway might have potential as a therapeutic strategy for prevention of skeletal muscle atrophy.

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Section: Activation Of Il-6/jak/stat3 Signaling Pathway In Denervated Skeletal Muscle Atrophymentioning

confidence: 94%

Inhibition of IL-6/JAK/STAT3 pathway rescues denervation-induced skeletal muscle atrophy

Huang¹,

Zhong²,

Zhu³

et al. 2020

Ann Transl Med

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“…In addition, Pal et al (2016) reported that oral administration of creatine (150 mg/kg BW per day) for 10 consecutive days resulted in significant regression of tumor size in Sarcoma-180 tumor-bearing mice and improved the overall survival of the animals. Furthermore, creatine supplementation (1 g/kg BW per day for 21 days) to Walker-256 tumor-bearing rats prevented skeletal muscle atrophy by attenuating systemic inflammation and protein degradation signaling, thereby enhancing their muscle mass and survival (Cella et al 2019). Similar beneficial effects of creatine supplementation have been obtained for humans with cancers (Fairman et al 2019).…”

Section: Health Benefits Of Creatine Supplementationmentioning

confidence: 72%

Important roles of dietary taurine, creatine, carnosine, anserine and 4-hydroxyproline in human nutrition and health

2020

Amino Acids

352

192

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Taurine (a sulfur-containing β-amino acid), creatine (a metabolite of arginine, glycine and methionine), carnosine (a dipeptide; β-alanyl-l-histidine), and 4-hydroxyproline (an imino acid; also often referred to as an amino acid) were discovered in cattle, and the discovery of anserine (a methylated product of carnosine; β-alanyl-1-methyl-l-histidine) also originated with cattle. These five nutrients are highly abundant in beef, and have important physiological roles in anti-oxidative and antiinflammatory reactions, as well as neurological, muscular, retinal, immunological and cardiovascular function. Of particular note, taurine, carnosine, anserine, and creatine are absent from plants, and hydroxyproline is negligible in many plant-source foods. Consumption of 30 g dry beef can fully meet daily physiological needs of the healthy 70-kg adult human for taurine and carnosine, and can also provide large amounts of creatine, anserine and 4-hydroxyproline to improve human nutrition and health, including metabolic, retinal, immunological, muscular, cartilage, neurological, and cardiovascular health. The present review provides the public with the much-needed knowledge of nutritionally and physiologically significant amino acids, dipeptides and creatine in animal-source foods (including beef). Dietary taurine, creatine, carnosine, anserine and 4-hydroxyproline are beneficial for preventing and treating obesity, cardiovascular dysfunction, and ageing-related disorders, as well as inhibiting tumorigenesis, improving skin and bone health, ameliorating neurological abnormalities, and promoting well being in infants, children and adults. Furthermore, these nutrients may promote the immunological defense of humans against infections by bacteria, fungi, parasites, and viruses (including coronavirus) through enhancing the metabolism and functions of monocytes, macrophages, and other cells of the immune system. Red meat (including beef) is a functional food for optimizing human growth, development and health.

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“…In Walker-256 tumor-bearing rats increased systemic inflammation was observed with animals presenting elevated plasma TNF-α and IL-6 compared to non-tumor-bearing control animals (Cella et al, 2020). These also showed increased gene expression and protein levels of MuRF1 and Atrogin-1 in hind limb muscles (Cella et al, 2020). Similar observations were reported in an orthotopic mouse model of bladder cancer, in which increased levels of inflammatory cytokines TNF-α, IL-6, and IL-1β, and activation of pro-inflammatory pathways including NF-κB were detected in muscles of urothelial tumor-bearing animals.…”

Section: Associations Between Systemic Inflammation and Cachexia In Dmentioning

confidence: 96%

“…In murine cancer cachexia models, the concurrent presence of systemic inflammation and loss of muscle and fat tissue has extensively been document. In Walker-256 tumor-bearing rats increased systemic inflammation was observed with animals presenting elevated plasma TNF-α and IL-6 compared to non-tumor-bearing control animals (Cella et al, 2020). These also showed increased gene expression and protein levels of MuRF1 and Atrogin-1 in hind limb muscles (Cella et al, 2020).…”

Section: Associations Between Systemic Inflammation and Cachexia In Dmentioning

confidence: 98%

Inflammation and Skeletal Muscle Wasting During Cachexia

et al. 2020

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Cachexia is the involuntary loss of muscle and adipose tissue that strongly affects mortality and treatment efficacy in patients with cancer or chronic inflammatory disease. Currently, no specific treatments or interventions are available for patients developing this disorder. Given the well-documented involvement of pro-inflammatory cytokines in muscle and fat metabolism in physiological responses and in the pathophysiology of chronic inflammatory disease and cancer, considerable interest has revolved around their role in mediating cachexia. This has been supported by association studies that report increased levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in some, but not all, cancers and in chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis (RA). In addition, preclinical studies including animal disease models have provided a substantial body of evidence implicating a causal contribution of systemic inflammation to cachexia. The presence of inflammatory cytokines can affect skeletal muscle through several direct mechanisms, relying on activation of the corresponding receptor expressed by muscle, and resulting in inhibition of muscle protein synthesis (MPS), elevation of catabolic activity through the ubiquitin-proteasomal system (UPS) and autophagy, and impairment of myogenesis. Additionally, systemic inflammatory mediators indirectly contribute to muscle wasting through dysregulation of tissue and organ systems, including GCs via the hypothalamus-pituitary-adrenal (HPA) axis, the digestive system leading to anorexia-cachexia, and alterations in liver and adipocyte behavior, which subsequently impact on muscle. Finally, myokines secreted by skeletal muscle itself in response to inflammation have been implicated as autocrine and endocrine mediators of cachexia, as well as potential modulators of this debilitating condition. While inflammation has been shown to play a pivotal role in cachexia development, further understanding how these cytokines contribute to disease progression is required to reveal biomarkers or diagnostic tools to help identify at risk patients, or enable the design of targeted therapies to prevent or delay the progression of cachexia.

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Creatine supplementation in Walker-256 tumor-bearing rats prevents skeletal muscle atrophy by attenuating systemic inflammation and protein degradation signaling

Cited by 37 publications

References 49 publications

Inhibition of IL-6/JAK/STAT3 pathway rescues denervation-induced skeletal muscle atrophy

Inhibition of IL-6/JAK/STAT3 pathway rescues denervation-induced skeletal muscle atrophy

Important roles of dietary taurine, creatine, carnosine, anserine and 4-hydroxyproline in human nutrition and health

Inflammation and Skeletal Muscle Wasting During Cachexia

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