How does a muscle "know" that it has been loaded and decides to grow? One of the answers offered by physiology is related to the mechano-growth factor — MGF. The editors explain this mechanism through a simple analogy with a construction site, and then show which links in the chain are supported by research and which remain hypothesis.
Analogy: construction site in muscle
Let's imagine a muscle fiber as a big building, and heavy training - as small damages in its walls. To renovate and even expand a building, you need two things: workers and building materials. The workers are satellite cells, the stem cells of the muscle, which usually "sleep" on the surface of the fiber.
In this analogy, the MGF plays the role of the foreman who is the first to arrive at the site after the damage and summons the workers. He does not build himself - his task is to increase the number of workers. Mature IGF-1 is already an engineer who organizes the construction itself: embeds new workers in the walls and starts protein synthesis.
This sequence — first to increase the number of progenitor cells, then to transform them into part of the fiber — is the essence of the hypothesis formulated by Goldspink's group (Goldspink, 2005). The model proposes why the body needs two different products of the same gene.
The analogy is, of course, simplified. Dozens of signals work simultaneously in real muscle: mechanosensitive proteins, inflammatory cells, hormones, growth factors. MGF is only one link in this picture, and as we will see below, its meaning is still debated.
Step 1: From load to signal
The first step is the conversion of mechanical force into a biochemical signal. Muscle cells experience stretching and tension through protein complexes connecting the inner skeleton of the fiber with its sheath and intercellular matrix. When these structures are deformed, signaling cascades are triggered in the cell.
Some of these signals affect how the IGF-1 gene is "read". There is one gene, but different versions of messenger RNA can be assembled from it, including or omitting certain sections. After loading or damage to the muscle, according to animal studies, the balance shifts towards the variant encoding MGF (in humans, the IGF-1Ec isoform).
This process is called alternative splicing. In simple words, the cell edits the "recipe" of the protein: the main part - mature IGF-1 - remains the same, and only the short "tail", the E-peptide, changes. It is this tail that distinguishes MGF from other forms.
Importantly, the increase in MGF is a local event. It is produced in the stressed muscle itself and is not a systemic hormone like growth hormone or hepatic IGF-1, which circulates in the blood. That is why it is measured not in blood, but in muscle biopsies — as mRNA.
Step 2: Satellite cells wake up
Satellite cells are the key to long-term muscle growth and recovery. A muscle fiber is a giant cell with many nuclei, and each nucleus "serves" a limited volume of cytoplasm. For the fiber to grow significantly, it needs new nuclei, and it is the satellite cells that supply them.
The life cycle of a satellite cell includes several stages:
- Idle - the cell is inactive and waiting for a signal.
- Activation - in response to damage or stress, the cell "wakes up".
- Proliferation — the cell divides to form a pool of myoblasts.
- Differentiation — myoblasts acquire features of muscle cells.
- Fusion - Myoblasts embed themselves into a damaged or growing fiber by adding nuclei.
MGF is hypothesized to act at the stages of activation and proliferation. Hill and Goldspink (2003) in experiments on rodents reported that after local muscle damage, the increase in MGF expression coincides with the activation of satellite cells and precedes the increase in the main form of IGF-1.
In human cell culture, Kandalla et al (2011) described that the synthetic E-peptide MGF increased the ability of muscle progenitor cells to fuse, including in cells obtained from humans of various ages. However, these are laboratory conditions with a controlled peptide concentration, not an organism.
Interestingly, in a study by Hameed et al. (2003), the increase in MGF mRNA after strength training was weaker in the elderly than in the young. This is consistent with the idea that the age-related decline in the muscle's ability to repair itself may be partially related to this link, although there is no direct evidence of causality.
MGF and mature IGF-1: who is responsible for what
Mature IGF-1, regardless of which isoform it is formed from, acts through the IGF-1 receptor on the cell surface. This receptor triggers the well-studied PI3K–Akt–mTOR pathway, which stimulates protein synthesis and inhibits its degradation (Schiaffino, Mammucari, 2011). This is the main "anabolic" branch of the IGF-1 system.
Regarding the MGF E-peptide, the situation is less clear. Yang and Goldspink (2002) reported that synthetic Ec-peptide stimulates myoblast proliferation but inhibits their differentiation, unlike mature IGF-1. The authors suggested that the peptide may act through another, as yet unidentified, mechanism.
An alternative hypothesis was proposed by the Barton group: E-peptides may not have their own receptor, but instead modulate the action of IGF-1 itself — in particular, affect how mature IGF-1 enters cells and activates its receptor (Pfeffer et al., 2009). In this case, MGF is not an independent factor, but an "amplifier" of the main signal.
| Characteristics | Mature IGF-1 | MGF E-peptide |
|---|---|---|
| Receptor | IGF-1 receptor, well studied | Not established; possibly acting through modulation of IGF-1 |
| Main pathway | PI3K–Akt–mTOR | Subject of discussion |
| Main effect | Protein synthesis, differentiation | Probably proliferation of progenitor cells |
| Time after loading | Later, longer | Earlier, short-term (according to mRNA data) |
| Reliability of data | High | Controversial |
This is important for understanding synthetic products: if the E-peptide acts only as an IGF-1 modulator within the tissue, then injecting an isolated short fragment elsewhere in the body may not reproduce the natural effect at all.
Weaknesses of the hypothesis
Goldspink's model is attractive but has several significant limitations. First, most of the data in humans is for mRNA, not protein. An increase in mRNA does not always mean a proportional increase in the corresponding peptide in the tissue, and reliable methods for measuring free Ec-peptide in human muscle are lacking.
The second is reproducibility. Fornaro et al (2014) from the pharmaceutical company Novartis tested a synthetic MGF peptide on mouse, human myoblasts and primary muscle stem cells and found no effect on either proliferation or differentiation. These results directly contradict earlier data.
Third, different laboratories used different versions of the peptide: different lengths, with amino acid substitutions for stability, with different end modifications. It is difficult to compare such results with each other, and even more so to transfer them to market products.
The fourth limitation concerns systemic administration. Natural MGF-related signaling is studied in the local muscle environment. Injecting a synthetic fragment or a pegylated form produces a different distribution; adequate delivery to human satellite cells and clinical benefit have not been established.
Editorial conclusions
Simply put, MGF is an "alarm" signal that a muscle is hypothesized to send immediately after exercise to summon satellite cells. Subsequently, mature IGF-1 takes over the baton, which controls protein synthesis and the incorporation of new nuclei into the fiber.
It has been reliably established that mechanical stress changes IGF-1 gene splicing and that satellite cells are important for muscle growth. It is less reliable — that the MGF E-peptide has its own activity independent of IGF-1.
The results of independent laboratories are contradictory, and there is no data on the effect of the synthetic peptide when administered to humans. Therefore, the mechanism that sounds convincing on the diagram cannot be considered as proof of the product's effectiveness.
To learn more, read our review of MGF: What is a Peptide and How Does It Work, an article on the results of MGF studies in humans and animals, and an article on the role of satellite cells in muscle growth.
References
- Goldspink G. Mechanical signals, IGF-I gene splicing, and muscle adaptation. Physiology (Bethesda). 2005;20:232–238.
- Hill M, Goldspink G. 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. J Physiol. 2003;549(Pt 2).
- Yang SY, Goldspink G. Different roles of the IGF-I Ec peptide (MGF) and mature IGF-I in myoblast proliferation and differentiation. FEBS Lett. 2002;522(1–3):156–160.
- Hameed M, Orrell RW, Cobbold M, et al. Expression of IGF-I splice variants in young and old human skeletal muscle after high resistance exercise. J Physiol. 2003;547(Pt 1):247–254.
- Kandalla PK, Goldspink G, Butler-Browne G, Mouly V. Mechano Growth Factor E peptide (MGF-E), derived from an isoform of IGF-1, activates human muscle progenitor cells and induces an increase in their fusion potential at different ages. Mech Ageing Dev. 2011;132(4).
- Pfeffer LA, Brisson BK, Lei H, Barton ER. The insulin-like growth factor (IGF)-I E-peptides modulate cell entry of the mature IGF-I protein. Mol Biol Cell. 2009;20(17).
- Schiaffino S, Mammucari C. Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skelet Muscle. 2011;1(1):4.
- Fornaro M, Hinken AC, Needle S, et al. Mechano-growth factor peptide, the COOH terminus of unprocessed insulin-like growth factor 1, has no apparent effect on myoblasts or primary muscle stem cells. Am J Physiol Endocrinol Metab. 2014;306(2):E150–E156.
