Impaired exercise training-induced muscle fiber hypertrophy and Akt/mTOR pathway activation in hypoxemic patients with COPD

Exercise training (ExTr) is largely used to improve functional capacity of chronic obstructive pulmonary disease (COPD) patients. However, ExTr partially restores muscle function in COPD patients, suggesting that confounding factors may limit the efficiency of ExTr. In the present study, we hypothesized that skeletal muscle adaptations triggered by ExTr could be compromised in hypoxemic COPD patients. Vastus lateralis muscle biopsies were obtained from normoxemic (n = 15; resting arterial PO2 = 68.5 +/- 1.5 mm Hg) and hypoxemic (n = 8; resting arterial PO2 = 57.0 +/- 1.0 mm Hg) COPD patients before and after a 2 month-ExTr program. ExTr induced a significant increase in exercise capacity both in normoxemic and hypoxemic COPD patients. However, ExTr increased citrate synthase and lactate dehydrogenase enzyme activities only in skeletal muscle of normoxemic patients. Similarly, muscle fiber cross-sectional area and capillary-to-fiber ratio were only increased in normoxemic patients. Expression of atrogenes (MuRF1, MAFbx/Atrogin-1) and autophagy-related genes (Beclin, LC3, Bnip, Gabarapl) remained unchanged in both groups. The phosphorylation level of Akt (Ser473), GSK-3beta (Ser9) and p70S6k (Thr389), which was non-significantly increased in normoxemic patients in response to ExTr, was significantly decreased in hypoxemic patients. We further showed on C2C12 myotubes that hypoxia completely prevented IGF-1-induced phosphorylation of Akt, GSK-3beta and p70S6K. Together, our observations suggest a role for hypoxemia in the adaptive response of skeletal muscle of COPD patients to ExTr

Annexin A1 drives macrophage skewing to accelerate muscle regeneration through AMPK activation.

Understanding the circuits that promote an efficient resolution of inflammation is crucial to deciphering the molecular and cellular processes required to promote tissue repair. Macrophages play a central role in the regulation of inflammation, resolution, and repair/regeneration. Using a model of skeletal muscle injury and repair, herein we identified annexin A1 (AnxA1) as the extracellular trigger of macrophage skewing toward a pro-reparative phenotype. Brought into the injured tissue initially by migrated neutrophils, and then overexpressed in infiltrating macrophages, AnxA1 activated FPR2/ALX receptors and the downstream AMPK signaling cascade, leading to macrophage skewing, dampening of inflammation, and regeneration of muscle fibers. Mice lacking AnxA1 in all cells or only in myeloid cells displayed a defect in this reparative process. In vitro experiments recapitulated these properties, with AMPK-null macrophages lacking AnxA1-mediated polarization. Collectively, these data identified the AnxA1/FPR2/AMPK axis as an important pathway in skeletal muscle injury regeneration

TNF-α- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism

Additional filesInternational audienceUNLABELLED: ABSTRACT: BACKGROUND: Muscle atrophy associated with various pathophysiological conditions represents a major health problem, because of its contribution to the deterioration of patient status and its effect on mortality. Although the involvement of pro-inflammatory cytokines in this process is well recognized, the role of sphingolipid metabolism alterations induced by the cytokines has received little attention. RESULTS: We addressed this question both in vitro using differentiated myotubes treated with TNF-α, and in vivo in a murine model of tumor-induced cachexia. Myotube atrophy induced by TNF-α was accompanied by a substantial increase in cell ceramide levels, and could be mimicked by the addition of exogenous ceramides. It could be prevented by the addition of ceramide-synthesis inhibitors that targeted either the de novo pathway (myriocin), or the sphingomyelinases (GW4869 and 3-O-methylsphingomyelin). In the presence of TNF-α, ceramide-synthesis inhibitors significantly increased protein synthesis and decreased proteolysis. In parallel, they lowered the expression of both the Atrogin-1 and LC3b genes, involved in muscle protein degradation by proteasome and in autophagic proteolysis, respectively, and increased the proportion of inactive, phosphorylated Foxo3 transcription factor. Furthermore, these inhibitors increased the expression and/or phosphorylation levels of key factors regulating protein metabolism, including phospholipase D, an activator of mammalian target of rapamycin (mTOR), and the mTOR substrates S6K1 and Akt. In vivo, C26 carcinoma implantation induced a substantial increase in muscle ceramide, together with drastic muscle atrophy. Treatment of the animals with myriocin reduced the expression of the atrogenes Foxo3 and Atrogin-1, and partially protected muscle tissue from atrophy. CONCLUSIONS: Ceramide accumulation induced by TNF-α or tumor development participates in the mechanism of muscle-cell atrophy, and sphingolipid metabolism is a logical target for pharmacological or nutritional interventions aiming at preserving muscle mass in pathological situations

Annexin A1 drives macrophage skewing towards a resolving phenotype to accelerate the regeneration of muscle injury through AMPK activation

Understanding the circuits that promote an efficient resolution of inflammation is crucial to deciphering the molecular and cellular processes required to promote tissue repair. Macrophages play a central role in the regulation of inflammation, resolution and repair/regeneration. Using a model of skeletal muscle injury and repair, herein we identify Annexin A1 (AnxA1) as the extracellular trigger of macrophage skewing towards a pro-reparative phenotype. Brought into the injured tissue initially by migrated neutrophils, and then over-expressed in infiltrating macrophages, AnxA1 activates FPR2/ALX receptors and the downstream AMPK signalling cascade leading to macrophage skewing, dampening of inflammation and regeneration of muscle fibres. Mice lacking AnxA1 in all cells or in myeloid cells only display a defect in this reparative process. In vitro experiments recapitulated these properties, with AMPK null macrophages lacking AnxA1-mediated polarization. Collectively, these data identify the AnxA1/FPR2/AMPK axis as a novel pathway in skeletal muscle injury regeneration.This work was supported by CNRS, French Society of Myology and Wellcome Trust Programme Grant 086867/Z/08/Z. GJ was supported by Fondation pour la Recherche Medicale (Equipe FRM DEQ20140329495

Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer

The IL-6 family of cytokines consists of IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control of immune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly, distortion of these cytokine activities often promotes chronic disease and cancer; the pathological importance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer and review therapeutic strategies designed to manipulate these cytokines in disease

Tumour resection by stereotactic laser endoscopy

Recent advances in neuro-imaging have led to the early diagnosis of increasingly smaller and more deeply-seated tumours. Conventional neurosurgical techniques are often not satisfactory to deal with these lesions. The authors describe their preliminary experience with a prototype neuro-endoscope. The technical characteristics of the instrument and description of its use in performing stereotactic laser tumour resection are provided

[Postoperative quality of life for patients with a vestibular schwannoma].

OBJECTIVES: To determine the prognoses criteria of quality of life's impairment after vestibular schwannoma surgery. STUDY DESIGN: Our study includes retrospectively 104 consecutive patients operated between 1991 & 2000 of a vestibular schwannoma. Patients with bilateral tumors were not included, neither patients lost of follow-up. The french version of the Short Form-36 self assessment questionnaire was sent to all patients. RESULTS: The response rate was 68% (71 patients). The patients' postoperative quality of life was lower of the norm, especially for psychical dimensions. This impairing of health whatever age, tumor size, operative approach or follow-up time. Sex and 2nd surgery were the only factors associated with a lower score. Women had worse rating of physical functioning. CONCLUSION: To operate small tumors should not assume that the impact on patients'life would be necessary less than following the removal of larger tumors. Women should have particularly clear explications before surgery and while follow-up