IGF-1 and Neural Regenerative Properties

Insulin-like-growth factor 1 is an extremely popular peptide in the research world today due to its profound effects on tissues, and its ability to not increase the size and strength of muscle tissue, but also aid in the regeneration of tissues such as tendons and ligaments. We know that this amino chain is popular for having effects such as improving the lean body mass of mice, while also increasing the oxidation of adipose tissue (fat loss), and increasing muscular endurance in these studies.

For this reason, IGF-1 is now one of the most researched peptides out there. But you may not know is that this incredible peptide does not just stop there. Recent research has strengthened the long-time linked IGF-1 to nerve regeneration. This is a huge effect that cannot be overlooked. As we know, with aging comes a decrease in nerve regeneration. Loss of muscular control, motor skills, and decreased brain function are all due to the fact that our nervous connections simply “don’t work they way they used to” once we start getting into our older years. This makes IGF an incredibly interesting peptide. First, lets take a closer look at this peptide, with the most recent description in relation to the nervous study.

Insulin-like growth factor 1 (IGF-1) is a single-chain, 70-amino-acid polypeptide, with a molecular mass of 7.6 kDa, similar in structure to pro-insulin, and is highly conserved across species. IGF-1 plays a significant role in neuronal development, recovery from neuronal injury, neuronal survival, and neurite outgrowth following crush injury.

In vitro studies have suggested that IGF-1 is produced locally by non-neuronal cells following injury and stimulates regeneration. Hansson et al. first showed that IGF-1 is secreted from Schwann cells in an autocrine fashion after peripheral nerve injury. IGF-1 has been shown to affect multiple facets of Schwann cell function in vitro, which likely contributes to improved nerve regeneration, including proliferation, mobilization, myelination, and Schwann cell–axon interaction. IGF-1 knockout mice have defects in neurologic development.

In addition to impaired recovery from neuronal injuries. Thus, there is substantial evidence that IGF-1 plays a key role in neuromuscular recovery following injury. When looking at neurological regeneration, we have to understand why and how a nerve cell regenerates. From Recknor et. al. When a nerve axon is severed, the end still attached to the cell body is labeled the proximal segment, while the other end is called the distal segment.

After injury, the proximal end swells and experiences some retrograde degeneration, but once the debris is cleared, it begins to sprout axons and the presence of growth cones can be detected. The proximal axons are able to regrow as long as the cell body is intact, and they have made contact with the Schwann cells in the endoneurial channel. Human axon growth rates can reach 2 mm/day in small nerves and 5 mm/day in large nerves.

Axonal outgrowth is central to nerve regeneration, and IGF-1 is a well-documented promoter of motor neuron survival, axonal growth, and axonal branching. In the regenerating nerve, IGF-1 is a key promoter of initial sprouting and subsequent elongation of axons (for review, see Rabinovsky). Although there has been extensive investigation of the effect of IGF-1 on neuron outgrowth and survival, nearly all of the studies were performed in vitro or in embryonic animals. Thus, it is not known how increased age affects the neuronal response to IGF-1

Age and developmental stage are the major determinants of IGF-1 levels. IGF-1 levels peak during puberty, initiating and maintaining the pubertal growth spurt. Following the pubertal growth spurt, IGF-1 levels decline at a rate of approximately 14% per decade. With continued aging, IGF-1 concentrations fall to levels of 20–80% of values for young adults, concordant with the decline in functional recovery following nerve transection and repair in aged adults.

Given the wide-ranging effects of IGF-1 on nerve regeneration and the known decline in IGF-1 with age, it was sought to determine whether IGF-1 replacement would improve nerve regeneration in aged animals. Previously, it was found that increasing systemic IGF-1 via pulsatile growth hormone injection did not improve nerve regeneration (unpublished data). Thus, the purpose of this study was to examine the effects of IGF-1 locally delivered to a nerve transection site in aged rats, and to evaluate neuromuscular recovery, axonal regeneration, myelination, Schwann cell activity, and the resulting changes at the NMJ. The hypothesis was that age-related decline in neuromuscular recovery following transection would be ameliorated by IGF-1 administered to the regenerating nerve.

The researchers fitted the mice with subcutaneous pumps that would administer recombinant human IGF at a dose of 0.025 µg/h for a testing period of 6 weeks. What they found nothing sort of amazing. Most studies that looked at the effect of IGF in rats on nervous regeneration primarily looked at their effects in older rats, as when we thing about neurogenesis we normally pair it with aging. Thankfully, the researchers used both old and young, and found the following.

IGF-1 Quantitative Data

IGF-1 had a marked effect on both young and aged animals, increasing axon number, diameter, and density, in addition to increasing myelination. Quantitative data are presented in the graph I posted above. For the number of axons per nerve, IGF-1 increased total axon number in both young and aged animals; however, this was only statistically significant for aged animals. For axon density, IGF-1 increased axon density in both young and aged animals; however, this was only statistically significant for aged animals.

For average axonal diameter, there was a significant increase in average axonal diameter in both young and aged animals when they were treated with IGF-1. There was no difference between the young IGF-1 group and aged IGF-1 group for number of axons per nerve, axon density, and average axonal diameter. This data tells us that IGF-1 acts directly on the axons of nerve cells, and has a tremendous affect on the regeneration of the cell after an injury.

This backs up research such as Rus et. al. who proved that IGF-1 treatment was directly beneficial to the recovery of a damaged sciatic nerve in a rat. Vergani et al. found that systemic IGF-1 promoted neuronal survival following crush injury and improved muscle reinnervation. Kanje et al. found that locally delivered IGF-1 following crush injury in juveniles led to improved sensory function. Tiancgo et al. found that IGF-1 locally delivered to an end-to-side repair improved muscle function in young rats.

IGF-1 has always been my go-to peptide to research for its pronounced effects on the recovery of tissues. But I like many, had not taken to the time research how much it also benefits a rats nervous system. This data tells us really how beneficial this substance is in terms of recovery, proliferation, and growth. Overall, the study has provided substantial evidence that locally delivered IGF-1 improves neuromuscular recovery after nerve injury in aged animals.

It was showed that, when local IGF-1 levels were equally supplemented in young and aged animals, nerve regeneration and NMJ preservation were similar, suggesting that IGF-1 may be a contributing factor in age-related impairment of neuromuscular recovery. However, the study has not conclusively demonstrated that IGF-1 deficiency is the immediate cause of age-related impairments in neuromuscular recovery after injury.

Muscle Nerve. 2010 Mar;41(3):335-41. doi: 10.1002/mus.21485.
Effect of locally delivered IGF-1 on nerve regeneration during aging: an experimental study in rats.