110 research outputs found
Editorial: myokines, adipokines, cytokines in muscle pathophysiology
Individual striated muscle fibers communicate in both a paracrine and endocrine fashion and are
also involved in the crosstalk with other tissues and organs such as the adipose tissue, immune
system, liver, pancreas, bones, and brain (Delezie andHandschin, 2018). The striatedmuscle, which
accounts for 40% of bodymass, presents high biosynthetic activity, and extensive vascularization,
features that endorse current thinking that muscle is the largest endocrine system of the body
(Benatti and Pedersen, 2015). There are hundreds of muscle secretory products, collectively
known as myokines, including proteins, miRNA, and exosomes (Barone et al., 2016). Muscle
secretion is significantly affected by muscle contraction (Son et al., 2018) due to the activation
of mechanotransduction pathways (Coletti et al., 2016a). It has been suggested that the adipose
tissue is also an endocrine organ, producing adipokines- leptin, and other hormones, in addition to
cytokines (Galic et al., 2010). The inflammatory infiltrate in fat depots affects the course of several
diseases, including cancer (Batista et al., 2012; Sawicka and Krasowska, 2016; Neto et al., 2018;
Opatrilova et al., 2018), and an extensive review on the role of adipokines in disease has been
published elsewhere (Orzechowski et al., 2014).
Myokines, adipokines, and cytokines are major therapeutic targets in both muscular and
non-muscular diseases (Lindegaard et al., 2013;Manole et al., 2018), and understanding of their role
in tissue crosstalk represents a subject of great interest in current biology.We have therefore chosen
to address this paradigm within this Frontiers special issue on “Myokines, Adipokines, Cytokines
in Muscle Pathophysiology.
Tumor microenvironment autophagic processes and cachexia: the missing link?
Cachexia is a syndrome that affects the entire organism and presents a variable plethora of symptoms in patients, always associated with continuous and involuntary degradation of skeletal muscle mass and function loss. In cancer, this syndrome occurs in 50% of all patients, while prevalence increases to 80% as the disease worsens, reducing quality of life, treatment tolerance, therapeutic response, and survival. Both chronic systemic inflammation and immunosuppression, paradoxically, correspond to important features in cachexia patients. Systemic inflammation in cachexia is fueled by the interaction between tumor and peripheral tissues with significant involvement of infiltrating immune cells, both in the peripheral tissues and in the tumor itself. Autophagy, as a process of regulating cellular metabolism and homeostasis, can interfere with the metabolic profile in the tumor microenvironment. Under a scenario of balanced autophagy in the tumor microenvironment, the infiltrating immune cells control cytokine production and secretion. On the other hand, when autophagy is unbalanced or dysfunctional within the tumor microenvironment, there is an impairment in the regulation of immune cell’s inflammatory phenotype. The inflammatory phenotype upregulates metabolic consumption and cytokine production, not only in the tumor microenvironment but also in other tissues and organs of the host. We propose that cachexia-related chronic inflammation can be, at least, partly associated with the failure of autophagic processes in tumor cells. Autophagy endangers tumor cell viability by producing immunogenic tumor antigens, thus eliciting the immune response necessary to counteract tumor progression, while preventing the establishment of inflammation, a hallmark of cachexia. Comprehensive understanding of this complex functional dichotomy may enhance cancer treatment response and prevent/mitigate cancer cachexia. This review summarizes the recent available literature regarding the role of autophagy within the tumor microenvironment and the consequences eliciting the development of cancer cachexia
Human cachexia induces changes in mitochondria, autophagy and apoptosis in the skeletal muscle
Cachexia is a wasting syndrome characterized by the continuous loss of skeletal muscle mass due to imbalance between protein synthesis and degradation, which is related with poor prognosis and compromised quality of life. Dysfunctional mitochondria are associated with lower muscle strength and muscle atrophy in cancer patients, yet poorly described in human cachexia. We herein investigated mitochondrial morphology, autophagy and apoptosis in the skeletal muscle of patients with gastrointestinal cancer-associated cachexia (CC), as compared with a weight-stable cancer group (WSC). CC showed prominent weight loss and increased circulating levels of serum C-reactive protein, lower body mass index and decreased circulating hemoglobin, when compared to WSC. Electron microscopy analysis revealed an increase in intermyofibrillar mitochondrial area in CC, as compared to WSC. Relative gene expression of Fission 1, a protein related to mitochondrial fission, was increased in CC, as compared to WSC. LC3 II, autophagy-related (ATG) 5 and 7 essential proteins for autophagosome formation, presented higher content in the cachectic group. Protein levels of phosphorylated p53 (Ser46), activated caspase 8 (Asp384) and 9 (Asp315) were also increased in the skeletal muscle of CC. Overall, our results demonstrate that human cancer-associated cachexia leads to exacerbated muscle-stress response that may culminate in muscle loss, which is in part due to disruption of mitochondrial morphology, dysfunctional autophagy and increased apoptosis. To the best of our knowledge, this is the first report showing quantitative morphological alterations in skeletal muscle mitochondria in cachectic patients
The mechanical stimulation of myotubes counteracts the effects of tumor-derived factors through IL-4 secretion and the modulation of the activin/follistatin ratio
Exercise counteracts cachexia, but it is unclear to which extent
the exercise-dependent mechanical stimulation of muscle
per se plays a role in exercise beneficial effects. To study
the mechanisms underlying mechanical stimulation, we cultured
C2C12 myotubes in the absence or in the presence of
a cyclic mechanical stretching stimulus (MS) and in the absence
or presence of C26 tumour-derived factors (C26-CM),
so as to mimic the mechanical stimulation of exercise and
cancer cachexia, respectively. We found that C26-CM contains
activin and induces activin release by myotubes, further
exacerbating its negative effects, consisting in myotube atrophy
and in hampering myoblast recruitment and fusion into
myotubes. A high level of circulating activin is an adverse
prognostic factor in cancer patients, and our in vitro results
demonstrate that activin may be a direct player and not just
a marker of cachexia. We also found that MS is sufficient to
counteract the adverse tumour-mediated effects on muscle
cells, in association with an increased follistatin/activin ratio
in the cell culture medium, indicating that myotubes actively
release follistatin upon stretching. In addition, MS induces IL-
4 secretion by muscle cells. Recombinant follistatin counteracts
C26 tumour effects on myotubes exclusively by rescuing
fusion index, while recombinant IL-4 ameliorates fusion index,
as well as the myotube size, both in terms of myotube
diameter and number of nuclei per myotube. Our results indicate
that tumour cells negatively affect muscle cells by releasing
soluble factors and that MS is sufficient to
counteract these effects, by affecting the muscle secretome
with autocrine/paracrine pathways. Activin and Act-R ligands
are becoming increasingly important as triggers of muscle
wasting and as pharmacological targets to treat cachexia;
however, since follistatin alone is incapable to entirely block
the C26-CM effects, the development of novel activintargeted
approaches should consider the existence of further
significant tumour-secreted factors mediating cachexia
Acute exhaustive exercise regulates IL-2, IL-4 and MyoD in skeletal muscle but not adipose tissue in rats
Background: The purpose of this study was to evaluate the effect of exhaustive exercise on proteins associated with muscle damage and regeneration, including IL-2, IL-4 and MyoD, in extensor digitorum longus (EDL) and soleus muscles and mesenteric (MEAT) and retroperitoneal adipose tissues (RPAT). Methods: Rats were killed by decapitation immediately (E0 group, n = 6), 2 (E2 group, n = 6) or 6 (E6 group, n = 6) hours after the exhaustion protocol, which consisted of running on a treadmill at approximately 70% of VO(2max) for fifty minutes and then at an elevated rate that increased at one m/min every minute, until exhaustion. Results: The control group (C group, n = 6) was not subjected to exercise. IL-2 protein expression increased at E0 in the soleus and EDL; at E2, this cytokine returned to control levels in both tissues. In the soleus, IL-2 protein expression was lower than that in the control at E6. IL-4 protein levels increased in EDL at E6, but the opposite result was observed in the soleus. MyoD expression increased at E6 in EDL. Conclusion: Exhaustive exercise was unable to modify IL-2 and IL-4 levels in MEAT and RPAT. The results show that exhaustive exercise has different effects depending on which muscle is analysed.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Brazil)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil
Neurolysin knockout mice generation and initial phenotype characterization
The oligopeptidase neurolysin (EC 3.4.24.16; Nln) was first identified in rat brain synaptic membranes and shown to ubiquitously participate in the catabolism of bioactive peptides such as neurotensin and bradykinin. Recently, it was suggested that Nln reduction could improve insulin sensitivity. Here, we have shown that Nln knockout mice (KO) have increased glucose tolerance, insulin sensitivity and gluconeogenesis. KO mice have increased liver mRNA for several genes related to gluconeogenesis. Isotopic label semi-quantitative peptidomic analysis suggests increase in specific intracellular peptides in gastrocnemius and epididymal adipose tissue, which likely is involved with the increased glucose tolerance and insulin sensitivity in the KO mice. These results suggest the exciting new possibility that Nln is a key enzyme for energy metabolism and could be a novel therapeutic target to improve glucose uptake and insulin sensitivity
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