IGF-1 EC vs IFG-1 lr3
- 05-17-2008, 07:33 PM
- 05-17-2008, 11:24 PM
Both circulating IGF-1Ea synthesized in the liver, and tissue expressed IGF-1Ec are involved in the tissue repair process. This can be noted in studies that show expression of both IGF-1Ea as well as IGF-1Ec following damage to muscle tissue either from strenuous exercise or external injury. The action of both these isoforms is slightly different.
In short, IGF1-Ec is expressed 1st in response to tissue damage, and is responsible for stem cell proliferation and migration to the injury site. Its role here subsides as IGF-1Ea expression reaches it's maximum by this time and finishes the repair process.
Expression and splicing of the insulin-like growth factor gene in rodent muscle is associated with muscle satellite (stem) cell activation following local tissue damage
Maria Hill and Geoffrey Goldspink
Basic Medical Sciences and Department of Surgery, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK
Muscle satellite cells are mononuclear cells that remain in a quiescent state until activated when they proliferate and fuse with muscle fibres to donate nuclei, a process necessary for post-embryonic growth, hypertrophy and tissue repair in this post-mitotic tissue. These processes have been associated with expression of the insulin-like growth factor (IGF-I) gene that can undergo alternative splicing to generate different gene products with varying functions. To gain insight into the cellular mechanisms involved in local tissue repair, the time courses of expression of two IGF-I splice variants produced in muscle were determined together with marker genes for satellite cell activation following local muscle damage. Using real-time RT-PCR with specific primers, the mRNA transcripts in rat tibialis anterior muscles were measured at different time intervals following either mechanical damage imposed by electrical stimulation of the stretched muscle or damage caused by injection with bupivacaine. It was found that the autocrine splice variant mechano growth factor (MGF) was rapidly expressed and then declined within a few days following both types of damage. Systemic IGF-IEa was more slowly upregulated and its increase was commensurate with the rate of decline in MGF expression. Satellite cell activation as measured by M-cadherin and one of the muscle regulatory factors MyoD and the sequence of expression suggests that the initial pulse of MGF is responsible for satellite cell activation, as the systemic IGF-IEa mRNA expression peaks after the expression of these markers, including M-cadherin protein. Later splicing of the IGF-I gene away from MGF but towards IGF-IEa seems physiologically appropriate as IGF-IEa is the main source of mature IGF-I for upregulation of protein synthesis required to complete the repair.
Growth factor delivery methods in the management of sports injuries: the state of play
IGF-1 has at least three isoforms: IGF-1Ea, IGF-1Eb and IGF-1Ec. IGF-1Ea is the circulating form of IGF-1, which is released from the liver, whereas IGF-1Ec, also known as mechano growth factor (MGF), is the tissue isoform released from skeletal muscle cells and is believed to exert exclusively autocrine/paracrine actions.(23)
The different isoforms have slightly different biological actions. IGF-1Ea is known to stimulate terminal differentiation of muscle cells into myotubes and promote stem cell-mediated muscle regeneration, whereas MGF is damage sensitive, controls local tissue repair and is more potent than IGF-1Ea at causing hypertrophy.(23) MGF is rapidly degraded in the serum.(23)
The sequencing of the human genome showed that there are only about 40,000 genes. However, there are many more proteins. This is because some genes are spliced to produce different protein/peptides which usually have different biological functions. Combining physiological and molecular biology methods made it possible to identify and characterize a local muscle growth/repair factor (MGF). After resistance exercise, the IGF-I gene is spliced towards MGF which kick starts hypertrophy and repair of local muscle damage by activating the muscle stem cells as well as anabolic processes. Interestingly, loss of muscle mass in old age and in certain diseases is associated with an impaired ability to express MGF.
Mechano Growth Factor (MGF) also known as IGF-1Ec is a growth factor/repair factor that is derived from exercised or damaged muscle tissue. MGF has been shown to boost muscle mass by improving the ability of wasted tissue to grow and improve itself by activating muscle stem cells and increasing the upregulation of protein synthesis. MGF is a part of the IGF family, but in the case of MGF, this part of the peptide acts as a separate growth factor involved in initiating muscle satellite (stem) cell activation in addition to its IGF-1 receptor domain which increases protein synthesis, and hence improves muscle mass. (Adams GR 2002).
Mechano Growth Factor (MGF) is derived from the insulin-like growth factor (IGF-I) but its sequence differs from the systemic IGF-I produced by the liver. MGF is expressed by mechanically overloaded muscle and is involved in tissue repair and adaptation. It is expressed as a pulse following muscle damage and is apparently involved in the activation of muscle satellite (stem) cells. These donate nuclei to the muscle fibers that are required for repair and for the hypertrophy processes which may have similar regulatory mechanisms. Hence, Mechano growth Factor (MGF) appears to be more anabolic than IGF because MGF responds to the signals produced by damaged muscle tissue induced by exercise and actually repairs the tissue and prevents cell death. Loss of muscle mass (sarcopenia) is one of the main problems associated with ageing as it has major health care as well as socioeconomic implications. The growth hormone (GH)/IGF-I axis is regarded as an important regulator of muscle mass. However, it is now appreciated that other tissues in addition to the liver express IGF-I and that there are local as well as systemic forms of IGF-I which have different functions.
At least two different kinds of IGF-I that are expressed by skeletal muscle are derived from the IGF-I gene by alternative splicing, one of which is expressed in response to physical activity which has now been called mechano growth factor(MGF). The other is similar to the systemic or liver type (IGF-IEa) and is important as the provider of mature IGF-I required for upregulating protein synthesis. MGF differs from systemic IGF-IEa in that it has a different peptide sequence which is responsible for replenishing the satellite (stem) cells in skeletal muscle, in other words it is more anabolic.
In vivo experiments in which muscles of the rat were subjected to mechanical damage or injection of a myotoxic agent also demonstrated (Hill &Goldspink, 2003) that MGF precedes muscle satellite (stem) cell activation. This is in accord with the finding that when skeletal muscle cells in culture, were either transfected with the MGF cDNA or were treated with the MGF carboxy peptide they increased in number but stayed as monocleated myoblasts (Yang & Goldspink, 2002.
It appears that MGF plays a dual role in inducing satellite cell activation as well as protein synthesis and this is probably why it is much more potent than the liver type or IGF-IEa for inducing rapid muscle hypertrophy. The ability to produce MGF declines with age, and this is commensurate with the decline in circulating GH levels. GH treatment up regulates the level of IGF-I gene expression in older people and when combined with resistance exercise more is spliced towards MGF and hence should improve the ability of muscle to respond to physical activity.(Goldspink and Harridge 2004). The characterization of a local tissue repair factor (mechano growth factor, MGF) that is produced by exercised and/or damaged muscle by differential splicing of the IGF-I gene provides understanding of how muscle is maintained in the young normal individual. Mechano Growth Factor, or MGF, is different to the systemic IGF-I as it has an insert of 49 base pairs in exon 5 that introduces a reading frame shift resulting in a C terminal peptide with unique properties. Muscle is a post-mitotic tissue and as cell replacement is not a means of tissue repair there has to be an efficient local repair mechanism otherwise the damaged cells undergo cell death. The extra nuclei for muscle repair and hypertrophy are provided by the muscle satellite (stem) cells. The pool of these stem cells is apparently replenished by the action of MGF, which is produced as a pulse following a mechanical challenge. Unfortunately, the production of MGF is deficient in certain diseases such as in the muscular dystrophies in which the mechanotransduction mechanism, which may involve the dystrophin complex, is defective. In elderly muscles, decreased levels of growth hormone apparently mean that there is less primary RNA transcript of the IGF-I gene to be spliced towards MGF. Consequently, there is an increasing inability to maintain muscle mass during ageing. Delivery of MGF and cDNA or peptide produces marked increases in the strength of normal as well as diseased muscle and, therefore, MGF has considerable potential as a generic means of treating muscle cachexia. (Goldspink 2006).
Skeletal muscle is one of the few tissues with the capacity for rapid and widespread repair. The source of this regenerative ability lies in precursor stem-cell reserves that are harbored by the myofibers. The myofibers (muscle fibers) that comprise skeletal muscle are muscle cells packed with contractile machinery (myofibrils), rechargeable energy sources (mitochondria), many nuclei (myonuclei), and a cytoplasmic unit (sarcoplasm, over two-thirds of which is water), each competing in a sense for space inside the cell. (Linstedt SL 1998). Mechano Growth Factor targets skeletal tissue, and promotes muscle growth by repairing the damaged tissue and upregulating protein synthesis.
05-18-2008, 12:19 AM
wow...thank you for the great info...
one last question (for now)...can the IGF-1 Ec be mixed using BW?
05-18-2008, 12:57 AM