Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation.

Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-ß superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors.

The cAMP response element binding protein (CREB) is activated by insulin-like growth factor-1 (IGF-1) and regulates myostatin gene expression in skeletal myoblast.

Myostatin, a member of the Transforming Growth Factor beta (TGF-ß) superfamily, plays an important role as a negative regulator of skeletal muscle growth and differentiation. We have previously reported that IGF-1 induces a transient myostatin mRNA expression, through the activation of the Nuclear Factor of Activated T cells (NFAT) in an IP3/calcium-dependent manner. Here we examined the activation of CREB transcription factor as downstream targets of IGF-1 during myoblast differentiation and its role as a regulator of myostatin gene expression. In cultured skeletal myoblast, IGF-1 induced the phosphorylation and transcriptional activation of CREB via IGF-1 Receptor/Phosphatidylinositol 3-Kinase (PI3K)/Phospholipase C gamma (PLC γ), signaling pathways. Also, IGF-1 induced calcium-dependent molecules such as Calmodulin Kinase II (CaMK II), Extracellular signal-regulated Kinases (ERK), Protein Kinase C (PKC). Additionally, we examined myostatin mRNA levels and myostatin promoter activity in differentiated myoblasts stimulated with IGF-1. We found a significant increase in mRNA contents of myostatin and its reporter activity after treatment with IGF-1. The expression of myostatin in differentiated myoblast was downregulated by the transfection of siRNA-CREB and by pharmacological inhibitors of the signaling pathways involved in CREB activation. By using pharmacological and genetic approaches together these data demonstrate that IGF-1 regulates the myostatin gene expression via CREB transcription factor during muscle cell differentiation.

[Bioethics in Peru]. / Bioética en el Perú.

Bioethics has still not acquired an identity of its own in Peru. The Ethics Committee of the Peruvian Medical School and the National AIDS Commission are review committees that deal with ethical problems arising in practice. Doubts regarding quality control of the drugs being tested have been raised in research on human subjects. Questions related to reproduction are very important. There is a high incidence of adolescent pregnancies, and illegal abortions result in many deaths and hospitalizations of women in serious condition. Birth control methods, such as vasectomy, conflict with attitudes about manhood in Peruvian society. Euthanasia is prohibited by the Ethical Code of the Peruvian Medical School, and legislation penalizes assisted suicide. Organ transplantation is hindered by concerns over early declaration of death. Handicapped children are often rejected by society owing to an absurd belief in the possibility that disorders such as Down's syndrome are contagious. The Ministry of Health requires state hospitals to accept AIDS patients, but instances of rejection are still reported.

Bioethics in Peru.

To date the application of bioethics in Peru has been rudimentary. The discipline has not yet acquired a distinct identity; only a few committees review ethical problems that arise in the course of medical practice, and bioethics is still taught mainly at schools of philosophy and theology. At the same time, situations in various health fields have raised bioethics questions or indicated areas where bioethical approaches might be effectively applied. Among others, the activities involved include research on human subjects, interventions relating to human reproduction, treatment of AIDS patients, treatment of dying patients, organ transplants, and management of handicapped children. This article reviews developments in each of these areas, with an eye to specific matters of ethical concern.