Review: Mechanical Signals, IGF-I Gene Splicing, and Muscle Adaptation
Geoffrey Goldspink. Physiology 20: 232-238, 2005
Combining physiological and molecular biology methods made it possible to identify and characterize a local muscle growth/repair factor (MGF). Following resistance exercise, MGF "kick starts" muscle hypertrophy and is important in local tissue repair. Loss of muscle mass in old age and certain diseases is associated with an impaired ability to express MGF.
And this looks like the initial report, back in 1999.
Changes in muscle mass and phenotype and the expression of autocrine and systemic growth factors by muscle in response to stretch and overload. Goldspink G. J Anat. ;194 ( Pt 3):323-34 (1999).
The study of the underlying mechanisms by which cells respond to mechanical stimuli, i.e. the link between the mechanical stimulus and gene expression, represents a new and important area in the morphological sciences. Several cell types ('mechanocytes'), e.g. osteoblasts and fibroblasts as well as smooth, cardiac and skeletal muscle cells are activated by mechanical strain and there is now mounting evidence that this involves the cytoskeleton. Muscle offers one of the best opportunities for studying this type of mechanotransduction as the mechanical activity generated by and imposed upon muscle tissue can be accurately controlled and measured in both in vitro and in vivo systems. Muscle is highly responsive to changes in functional demands. Overload leads to hypertrophy, whilst decreased load force generation and immobilisation with the muscle in the shortened position leads to atrophy. For instance it has been shown that stretch is an important mechanical signal for the production of more actin and myosin filaments and the addition of new sarcomeres in series and in parallel. This is preceded by upregulation of transcription of the appropriate genes some of which such as the myosin isoforms markedly change the muscle phenotype. Indeed, the switch in the expression induced by mechanical activity of myosin heavy chain genes which encode different molecular motors is a means via which the tissue adapts to a given type of physical activity. As far as increase in mass is concerned, our group have cloned the cDNA of a splice variant of IGF-1 that is produced by active muscle that appears to be the factor that controls local tissue repair, maintenance and remodelling. From its sequence it can be seen that it is derived from the IGF-1 gene by alternative splicing but it has different exons to the liver isoforms. It has a 52 base insert in the E domain which alters the reading frame of the 3' end. Therefore, this splice variant of IGF-1 is likely to bind to a different binding protein which exists in the interstitial tissue spaces of muscle, neuronal tissue and bone. This would be expected to localise its action as it would be unstable in the unbound form which is important as its production would not disturb the glucose homeostasis unduly. This new growth factor has been called mechano growth factor (MGF) to distinguish it from the liver IGFs which have a systemic mode of action. Although the liver is usually thought of as the source of circulating IGF-1, it has recently been shown that during exercise skeletal muscle not only produces much of the circulating IGF-1 but active musculature also utilises most of the IGF-I produced. We have cloned both an autocrine and endocrine IGF-1, both of which are upregulated in cardiac as well as skeletal muscle when subjected to overload. It has been shown that, in contrast to normal muscle, MGF is not detectable in dystrophic mdx muscles even when subjected to stretch and stretch combined with electrical stimulation. This is true for muscular dystrophies that are due to the lack of dystrophin (X-linked) and due to a laminin deficiency (autosomal), thus indicating that the dystrophin cytoskeletal complex may be involved in the mechanotransduction mechanism. When this complex is defective the necessary systemic as well as autocrine IGF-1 growth factors required for local repair are not produced and the ensuing cell death results in progressive loss of muscle mass. The discovery of the locally produced IGF-1 appears to provide the link between the mechanical stimulus and the activation of gene expression.
Looks like it has variable and unique mechanisms of regulation.
Mechanical signal transduction in skeletal muscle growth and adaptation. Tidball JG.J Appl Physiol. 98(5):1900-8 (2005).
The adaptability of skeletal muscle to changes in the mechanical environment has been well characterized at the tissue and system levels, but the mechanisms through which mechanical signals are transduced to chemical signals that influence muscle growth and metabolism remain largely unidentified. However, several findings have suggested that mechanical signal transduction in muscle may occur through signaling pathways that are shared with insulin-like growth factor (IGF)-I. The involvement of IGF-I-mediated signaling for mechanical signal transduction in muscle was originally suggested by the observations that muscle releases IGF-I on mechanical stimulation, that IGF-I is a potent agent for promoting muscle growth and affecting phenotype, and that IGF-I can function as an autocrine hormone in muscle. Accumulating evidence shows that at least two signaling pathways downstream of IGF-I binding can influence muscle growth and adaptation. Signaling via the calcineurin/nuclear factor of activated T-cell pathway has been shown to have a powerful influence on promoting the slow/type I phenotype in muscle but can also increase muscle mass. Neural stimulation of muscle can activate this pathway, although whether neural activation of the pathway can occur independent of mechanical activation or independent of IGF-I-mediated signaling remains to be explored. Signaling via the Akt/mammalian target of rapamycin pathway can also increase muscle growth, and recent findings show that activation of this pathway can occur as a response to mechanical stimulation applied directly to muscle cells, independent of signals derived from other cells. In addition, mechanical activation of mammalian target of rapamycin, Akt, and other downstream signals is apparently independent of autocrine factors, which suggests that activation of the mechanical pathway occurs independent of muscle-mediated IGF-I release.
Muscle satellite (stem) cell activation during local tissue injury and repair.Hill M, Wernig A, Goldspink G. J Anat. 2003 Jul;203(1):89-99
In post-mitotic tissues, damaged cells are not replaced by new cells and hence effective local tissue repair mechanisms are required. In skeletal muscle, which is a syncytium, additional nuclei are obtained from muscle satellite (stem) cells that multiply and then fuse with the damaged fibres. Although insulin-like growth factor-I (IGF-l) had been previously implicated, it is now clear that muscle expresses at least two splice variants of the IGF-I gene: a mechanosensitive, autocrine, growth factor (MGF) and one that is similar to the liver type (IGF-IEa). To investigate this activation mechanism, local damage was induced by stretch combined with electrical stimulation or injection of bupivacaine in the rat anterior tibialis muscle and the time course of regeneration followed morphologically. Satellite cell activation was studied by the distribution and levels of expression of M-cadherin (M-cad) and related to the expression of the two forms of IGF-I. It was found that the following local damage MGF expression preceded that of M-cad whereas IGF-IEa peaked later than M-cad. The evidence suggests therefore that an initial pulse of MGF expression following damage is what activates the satellite cells and that this is followed by the later expression of IGF-IEa to maintain protein synthesis to complete the repair.
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#2 03-20-2006, 06:34 PM
Ronn Offline
Vet Join Date: Jul 2005
Location: Midwest
Posts: 65
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So everyone here understands up-front: I know virtually nothing about this compound. However it appears the answers to some of the questions being asked regarding MGF could be directly deduced from IGF1 information already available. And that is how I shall proceed with the following ‘advice’ on dosage, reconstitution and use.
Dosage: One could assume that since the MGF is the active agent in IGF1, a lesser dosage protocol may be in order. However, I think it best to error on the side of what we know, rather than what we assume. Therefore, I would imagine a good starting point to be the bottom end of the IGF1 r3 dosage protocol; i.e. 40mgs daily.
How to measure: Unless you've tried IGF1 before, you're in for a real surprise when you try to measure out MCGS--very small dosages indeed. A slin pin to the instrument of choice, I would strongly suggest a 1/2 cc or even 3/10 cc over the full 1 cc (100 IU) pin.
How to reconstitute: IFB sells it's MFG in 1 mg vials (similar to IGF1), to reconstitute I'd suggest 1cc of Acetic Acid solution. Other compound have been suggested, however I feel the research points to AA as a superior choice for long shelf life after reconstitution.
Inject 1ml of AA solution into your vial of MGF, be cautious of the vacuum in the MFG vial. You will need to control the syringe plunger so the AA does not forcefully spray down onto the MGF powder (assuming it is as delicate as IGF). I would suggest 'venting' the vial first to release this vacuum. You want to trickle it down the side of the vial slowly and then swirl the solution gently to mix it into a clear solution.
Now you have 1cc of MFG and a concentration of 1000mcgs per cc (or 1mg per cc). Or in terms of your 100-IU slin pin, 100 IU’s equal 1000mcgs—get it? Now, An IU-100 slin pin has 50 marks on the barrel and is numbered 10IU through 100IU. So each mark- or "tick" as they are sometimes referred to--equals 20mcgs. As you can see, on a 100 IU pin this makes dosing VERY challenging.
Going to a small pin allows for easier measurements. Again, you solution is at 1000mcgs per cc --or in terms of your slin pin: 1000mcgs = 100IU. So you can covert "ticks" to mcgs via simple math on pins that only have 50 IU (1/2 cc pin) or 30 IU (3?10 cc pins).
Usage: I would guess injected post workout, IM bilaterally, into those muscles trained during that session. AA is quite painful when injected, so be ready. You can cut the solution with biostatic (sterile water)—about 2 to 3 times water to MGF will cut the pain. Just don’t get water into the NGF vial.
Let's build on this thread, created a central point for information grading the uses of this interesting new compound.
Hope this helps,
Ronn