Insulin-Like Growth Factor-1 and the

BodyJahzelle Ambus, Delany Brown, Christi

Burshek, Preston Crenshaw, Jordan Drake

IGF-1 is a polypeptide hormone made up of seventy amino

acids Sourced from the liver. Similar in structure to the hormone insulin, from which it

gets its name It operates not just in an endocrine manner but is also

believed to operate in a paracrine and autocrine fashion as well.

Received by a transmembrane receptor similar in structure to an insulin receptor, but with a higher affinity for IGF-1.

Expression of IGF-1 gene is insulin dependent

The Hormone

Promotes hypoglycemia and controls carbohydrate

metabolism and glycogen synthesis Insulin like effect

Also thought to affect lipolysis, enabling use of free fatty acids Regulated in adipocytes by GH Suggested due to research on patients with GH insensitivity

syndrome Increase in muscle hypertrophy

causes an increase in protein synthesis a decrease in protein degradation Due to combined properties of GH and insulin

Promotes increase in collagen synthesis thought to control the actions of growth hormone May regulate myoblast differentiation via miRNAs

Function of IGF-1

The Role of IGF-1 in the

BodyGlycogen synthesis

Lipid oxidation

Protein synthesis

Protein degradation

Collagen synthesis

Guha et al. (2013)

1. IGF-1 binds to the receptor IGF-1R

2. this activates PI3K, which produces PIP3, which in turn activates Akt

3. Akt controls protein synthesis via mTOR pathway

4. Akt also blocks GSK3β, which would normally block protein synthesis

5. AKT blocks protein degradation by inactivating Fox0 transcription factors

This pathway is how IGF-1 leads to increased muscle mass.

How it Operates

Hitachi et al. (2014)

MiRNAs help regulate skeletal muscle by helping control gene expression

Help degrade mRNA Inhibit translationThese particular miRNAs target the IGF-1 pathway: MiRNA-128a: has potential to

increase muscle mass by acting as a negative regulator

MiRNA-486: plays a role in connecting sarcomeres to the sarcoplasm by producing Ank1.5, helps regulate Akt by targeting PTEN, decreases PTEN and Fox01

MiRNA-199a-3p: regulates myogenesis by targeting certain molecules in IGF-1 pathway

The Role of MicroRNAs

Hitachi et al. (2014), Jia et al, (2014)

The role of IGF-1 begins

after muscle have been broken down or damaged following exercise.

IGF-1 acts on satellite cells, which are centrally involved with muscle growth and repair.

IGF-1 and satellite cells colocalize after a bout of acute exercise. Grubb et. al (2014)

A study done by Fragala et. al (2014), suggests that IGF-1R on leukocytes facilitates muscle recovery.

Exercise and IGF-1

What types of exercise

influence this response? Resistance training Aerobic Anaerobic

Generally, the intensity of the exercise is more relevant to this process than the type.

Exercise and IGF-1

Adaptions to exercise

Neural adaptions Increased rate coding Increased motor recruitment Increase in neural drive

Uptake of IGF-1 by hippocampus stimulates neurogenesis. Pareja –Galeana et. al (2013)

Anatomical adaptions Hypertrophy

Increases protein synthesis Decreases protein

degradation

Exercise and IGF-1

IGF-1-Akt pathway

is essential for muscle growth.

Induces hypertrophy and blocks atrophy

Exercise & IGF-1

Greater risk for neural degeneration and related

diseases, such as Alzheimer's and Dementia; as well as seizers.

Increased susceptibility to fibromyalgia, high BMI, and fatigue, all of which contribute to a decreased ability to exercise.

Effect the central bodily systems and shows side effects such as increased fluid retention, hypoglycemia, lipohypertrophy, increase in liver and kidney size and function, and acromegaly

When Proper Function is impaired.

A Lack of the hormone can be seen by maleffects

throughout the body. Neural

Because IGF-1 plays a role in neural plasticity and increased neural regeneration, when it is lacking, neural degeneration can exceed the rate of regenerations. This leads to increased risk of major brain diseases.

In addition to its protagonistic role in the creation of neurons, it also aids in the clearance of amyloid beta (Aβ), a protein central in the Alzheimer’s disease.

Low IGF-1 Levels

Doi et. al. (2015)

Muscular

Due to the body’s inability to effectively synthesis protein without IGF-1, muscle destruction could occur faster than it is being replaced. Muscle atrophy, fibromyalgia, premature fatigue

and pain.

Low IGF-1 Levels

Bjersing et al. (2013)

Due to its difficulty to track, IGF-1 is becoming an

increasingly popular substance to abuse. However, excess of the hormone can be equally dangerous as a lack.

Abusive supplementation of IGF-1 is associated with: Hypoglycemia, seizures, jaw pain, myalgia and fluid retention.

IGF-1 in addition to its binding protein Lipohypertrophy (higher BMI), headaches, increased liver and

kidney size and altered liver function. Those who abuse IGF-1 and it’s binding protein also may have

acromegaly, or at least display many of its symptoms. Damaged cardiac muscle structure and performance, cardiac

valve dysfunction and reduced VO2 max.

Excess IGF-1 and Doping

Dystrophin deficiency impacted by blunted IGF-1

response Post-natal impacts Myotubules and myofiber growth in adult tissues

Further Studies

Grounds et. al. (2012) http://www.nature.com/nm/journal/v10/n6/fig_tab/nm0604-584_F1.html

Paoli study on resistance training with protein

levels Focus: myostatin, IGF-1 and cytokine release Myostatin and IGF-1 inverse relationship and

downregulation P38 MAPK stress kinase Observing TNF-α High protein diet

Further Studies

Paoli et. al. (2015) http://www.biocarta.com/pathfiles/

m_p38mapkpathway.asp

Questions?

Bjersing, J. L., Erlandsson, M., Bokarewa, M. I., & Mannerkorpi, K. (2013). Exercise and obesity in fibromyalgia: beneficial roles of IGF-1 and resistin? Arthritis Research & Therapy. 15(1), R34.

Doi, T., Shimada, H., Makizako, H., Tsumimoto, K., Hotta, R., Nakakubo, S., & Suzuki, T. (2015). Association of insulin-like growth factor-1 with mild cognitive impairment and slow gait speed. Neurobiology Of Aging, 36(2), 942-947. doi:10.1016/j.neurobiolaging.2014.10.035

Grounds, M. D., & Shavlakadze, T. (2012). Growing muscle has different sarcolemmal properties from adult muscle: A proposal with scientific and clinical implications. Neuromuscular Disorders, 22(1), 890-892. doi: 10.1002/bies.201000136

Paoli, A., Pacelli, Q. F., Neri, M., Toniolo, L., Cancellara, P., Canato, M., Moro, T., Quadrelli, M., Morra, A., Faggian, D., Plebani, M., Bianco, A., & Reggiani, C. (2015). Protein supplementation increases postexercise plasma myostatin concentration after 8 weeks of resistance training in young physically active subjects. Journal of Medicinal Food, 18(1), 137-143. doi: 10.1089/jmf.2014.0004

Guha, N., Cowan, D. A., Sönksen, P. H., & Holt, R. I. (2013). Insulin-like growth factor-I (IGF-I) misuse in athletes and potential methods for detection. Analytical and bioanalytical chemistry, 405(30), 9669-9683.

Jia, L., Li, Y. F., Wu, G. F., Song, Z. Y., Lu, H. Z., Song, C. C., Zhang, Q. L., Zhu, J. Y., Yang, G. S., & Shi, X. E. (2014). MiRNA-199a-3p Regulates C2C12 Myoblast Differentiation through IGF-1/AKT/mTOR Signal Pathway. International Journal of Molecular Sciences, 15(1), 296-308. doi: 10.3390/ijms15010296

Keisuke, H., & Kunihiro, T. (2014). Role of microRNAs in skeletal muscle hypertrophy. Frontiers In Physiology, 4(5), 1-7. doi:10.3389/fphys.2013.00408

Selected References