Article

The pro-Forms of Insulin-Like Growth Factor I (IGF-I) Are Predominant in Skeletal Muscle and Alter IGF-I Receptor Activation

PhD, 240 South 40th Street, 441A Levy Building, Philadelphia, PA 19104. .
Endocrinology (Impact Factor: 4.64). 03/2013; 154(3):1215-24. DOI: 10.1210/en.2012-1992
Source: PubMed

ABSTRACT IGF-I is a key regulator of muscle development and growth. The pre-pro-peptide produced by the Igf1gene undergoes several posttranslational processing steps to result in a secreted mature protein, which is thought to be the obligate ligand for the IGF-I receptor (IGF-IR). The goals of this study were to determine what forms of IGF-I exist in skeletal muscle, and whether the mature IGF-I protein was the only form able to activate the IGF-IR. We measured the proportion of IGF-I species in murine skeletal muscle and found that the predominant forms were nonglycosylated pro-IGF-I and glycosylated pro-IGF-I, which retained the C-terminal E peptide extension, instead of mature IGF-I. These forms were validated using samples subjected to viral expression of IGF-I combined with furin and glycosidase digestion. To determine whether the larger molecular weight IGF-I forms were also ligands for the IGF-IR, we generated each specific form through transient transfection of 3T3 cells and used the enriched media to perform kinase receptor activation assays. Compared with mature IGF-I, nonglycosylated pro-IGF-I had similar ability to activate the IGF-IR, whereas glycosylation of pro-IGF-I significantly reduced receptor activation. Thus, it is important to understand not only the quantity, but also the proportion of IGF-I forms produced, to evaluate the true biological activity of this growth factor.

Download full-text

Full-text

Available from: Anastassios Philippou, Jun 27, 2015
0 Followers
 · 
287 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It is virtually undisputed that IGF-I promotes cell growth and survival. However, the presence of several IGF-I isoforms, vast numbers of intracellular signaling components, and multiple receptors results in a complex and highly regulated system by which IGF-I actions are mediated. IGF-I has long been recognized as one of the critical factors for coordinating muscle growth, enhancing muscle repair, and increasing muscle mass and strength. How to optimize this panoply of pathways to drive anabolic processes in muscle as opposed to aberrant growth in other tissues is an area that deserves focus. This review will address how advances in the bioavailability, potency, and tissue response of IGF-I can provide new potential directions for skeletal muscle therapeutics.
    Growth Hormone & IGF Research 10/2014; 24(5). DOI:10.1016/j.ghir.2014.06.003 · 1.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Insulin-like growth factor I (IGF-I) is a key regulator of muscle development and growth. The pre-pro-peptide produced by the Igf1 gene undergoes several post-translational processing steps to result in a secreted mature protein, which is thought to be the obligate ligand for the IGF-I receptor (IGF-IR). However, the significance of the additional forms and peptides produced from Igf1 is not clear. For instance, the C-terminal extensions called the E-peptides that are part of pro-IGF-I, have been implicated in playing roles in cell growth, including cell proliferation and migration and muscle hypertrophy in an IGF-IR independent manner. However, the activity of these peptides has been controversial. IGF-IR independent actions suggest the existence of an E-peptide receptor, yet such a protein has not been discovered. We propose a new concept: there is no E-peptide receptor, rather the E-peptides coordinate with IGF-I to modulate activity of the IGF-IR. Growing evidence reveals that the presence of an E-peptide alters IGF-I activity, whether as part of pro-IGF-I, or as a separate peptide. In this review, we will examine the past literature on IGF-I processing and E-peptide actions in skeletal muscle, address the previous attempts to separate IGF-I and E-peptide effects, propose a new model for IGF-I/E-peptide synergy, and suggest future experiments to test if the E-peptides truly modulate IGF-I activity.
    Frontiers in Endocrinology 03/2013; 4:42. DOI:10.3389/fendo.2013.00042
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteoarthritis (OA) is a common disease involving joint damage, an inadequate healing response and progressive deterioration of the joint architecture. Autologous blood-derived products, such as platelet-rich plasma (PRP), are key sources of molecules involved in tissue repair and regeneration. These products can deliver a collection of bioactive molecules that have important roles in fundamental processes, including inflammation, angiogenesis, cell migration and metabolism in pathological conditions, such as OA. PRP has anti-inflammatory properties through its effects on the canonical nuclear factor κB signalling pathway in multiple cell types including synoviocytes, macrophages and chondrocytes. PRP contains hundreds of different molecules; cells within the joint add to this milieu by secreting additional biologically active molecules in response to PRP. The net results of PRP therapy are varied and can include angiogenesis, the production of local conditions that favour anabolism in the articular cartilage, or the recruitment of repair cells. However, the molecules found in PRP that contribute to angiogenesis and the protection of joint integrity need further clarification. Understanding PRP in molecular terms could help us to exploit its therapeutic potential, and aid the development of novel treatments and tissue-engineering approaches, for the different stages of joint degeneration.
    Nature Reviews Rheumatology 10/2013; DOI:10.1038/nrrheum.2013.141 · 10.25 Impact Factor