Dataset Information

Molecular Mechanisms Responsible for the Rescue Effects of Pamidronate on Muscle Atrophy in Pediatric Burn Patients.

ABSTRACT: Not only has pamidronate been shown to prevent inflammation associated bone resorption following burn injury, it also reduces protein breakdown in muscle. The aim of this study was to identify the molecular mechanisms responsible for muscle mass rescue in pamidronate treated compared to placebo/standard of care-treated burn patients. Mature myotubes, generated by differentiating murine C2C12 myoblasts, were exposed for 48 h to 1 or 5% serum obtained from 3 groups of children: normal unburned, burned receiving standard of care, and burned receiving standard of care with pamidronate. Exposure to serum from burned patients caused dose-dependent myotube atrophy compared to normal serum as expected based on previous observations of muscle atrophy induced by burn injury in humans and animals. The size of C2C12 myotubes was partially protected upon exposure to the serum from patients treated with pamidronate correlating with the rescue of muscle size previously observed in these patients. At the molecular signaling level, serum from both pamidronate and non-pamidronate-treated burn patients increased pSTAT3/STAT3 and pERK1/2/ERK1/2 compared to normal serum with no significant differences between the two groups of burn patients indicating elevated production of inflammatory cytokines. However, serum from pamidronate-treated patients restored the phosphorylation of AKT and mTOR and reduced protein ubiquitination when compared to burn serum alone, suggesting a prevention of muscle catabolism and a restoration of muscle anabolism. Myotube atrophy induced by burn serum was partially rescued after exposure to a pan anti-TGF?-1/2/3 antibody, suggesting that this signaling pathway is partially responsible for the atrophy and that bisphosphonate protection of bones from resorption during burn injury prevents the release of muscle pro-catabolic factors such as TGF? into the circulation.

SUBMITTER: Pin F

PROVIDER: S-EPMC6692456 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular Mechanisms Responsible for the Rescue Effects of Pamidronate on Muscle Atrophy in Pediatric Burn Patients.

Pin Fabrizio F Bonetto Andrea A Bonewald Lynda F LF Klein Gordon L GL

Frontiers in endocrinology 20190807

Not only has pamidronate been shown to prevent inflammation associated bone resorption following burn injury, it also reduces protein breakdown in muscle. The aim of this study was to identify the molecular mechanisms responsible for muscle mass rescue in pamidronate treated compared to placebo/standard of care-treated burn patients. Mature myotubes, generated by differentiating murine C2C12 myoblasts, were exposed for 48 h to 1 or 5% serum obtained from 3 groups of children: normal unburned, bu ...[more]

PMID: 31447786

Similar Datasets

Project description:BACKGROUND:Blood transfusion is costly and associated with various medical risks. Studies in critically ill adult and pediatric patients suggest that implementation of more restrictive transfusion protocols based on lower threshold hemoglobin concentrations can be medically and economically advantageous. The purpose of this study was to evaluate the implications of a hemoglobin threshold change in pediatric burn patients. METHODS:We implemented a change in hemoglobin threshold from 10 g/dL to 7 g/dL and compared data from patients before and after this protocol change in a retrospective review. Primary endpoints were hemoglobin concentration at baseline, before transfusion, and after transfusion; amount of blood product administered; and mortality. Secondary endpoints were the incidence of sepsis based on the American Burn Association physiological criteria for sepsis and mean number of septic days per patient. All endpoint analyses were adjusted for relevant clinical covariates via generalized additive models or Cox proportional hazard model. Statistical significance was accepted at p less than 0.05. RESULTS:Patient characteristics and baseline hemoglobin concentrations (pre, 13.5 g/dL; post, 13.3 g/dL; p > 0.05) were comparable between groups. The group transfused based on the more restrictive hemoglobin threshold had lower hemoglobin concentrations before and after transfusion throughout acute hospitalization, received lower volumes of blood during operations (pre, 1012 mL; post, 824 mL; p < 0.001) and on days without surgical procedures (pre, 602 mL; post, 353 mL; p < 0.001), and had a lower mortality (pre, 8.0%; post, 3.9%; mortality hazard decline, 0.55 [45%]; p < 0.05). Both groups had a comparable incidence of physiological sepsis, though the more restrictive threshold group had a lower number of sepsis days per patient. CONCLUSION:More restrictive transfusion protocols are safe and efficacious in pediatric burn patients. The associated reduction of transfused blood may lessen medical risks of blood transfusion and lower economic burden. LEVEL OF EVIDENCE:Therapeutic, level IV.

Project description:Muscle disuse produces severe atrophy and a slow-to-fast phenotype transition in the postural Soleus (Sol) muscle of rodents. Antioxidants, amino-acids and growth factors were ineffective to ameliorate muscle atrophy. Here we evaluate the effects of nandrolone (ND), an anabolic steroid, on mouse skeletal muscle atrophy induced by hindlimb unloading (HU). Mice were pre-treated for 2-weeks before HU and during the 2-weeks of HU. Muscle weight and total protein content were reduced in HU mice and a restoration of these parameters was found in ND-treated HU mice. The analysis of gene expression by real-time PCR demonstrates an increase of MuRF-1 during HU but minor involvement of other catabolic pathways. However, ND did not affect MuRF-1 expression. The evaluation of anabolic pathways showed no change in mTOR and eIF2-kinase mRNA expression, but the protein expression of the eukaryotic initiation factor eIF2 was reduced during HU and restored by ND. Moreover we found an involvement of regenerative pathways, since the increase of MyoD observed after HU suggests the promotion of myogenic stem cell differentiation in response to atrophy. At the same time, Notch-1 expression was down-regulated. Interestingly, the ND treatment prevented changes in MyoD and Notch-1 expression. On the contrary, there was no evidence for an effect of ND on the change of muscle phenotype induced by HU, since no effect of treatment was observed on the resting gCl, restCa and contractile properties in Sol muscle. Accordingly, PGC1? and myosin heavy chain expression, indexes of the phenotype transition, were not restored in ND-treated HU mice. We hypothesize that ND is unable to directly affect the phenotype transition when the specialized motor unit firing pattern of stimulation is lacking. Nevertheless, through stimulation of protein synthesis, ND preserves protein content and muscle weight, which may result advantageous to the affected skeletal muscle for functional recovery.

Dataset Information

Molecular Mechanisms Responsible for the Rescue Effects of Pamidronate on Muscle Atrophy in Pediatric Burn Patients.

Publications

Molecular Mechanisms Responsible for the Rescue Effects of Pamidronate on Muscle Atrophy in Pediatric Burn Patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets