The IGF-IGFBP system in aerobic exercise : with focus on skeletal muscle

Activity induced skeletal muscle adaptation has been suggested to be mediated largely by intrinsic factors, such as insulin-like growth factor (IGF)-I. IGF-I stimulates muscle glucose and amino acid uptake and promotes anabolism. IGF-I is bound to a family of high affinity IGF binding proteins (IGFBP 1-6) which regulate access of systemic IGF-I to tissues and determines local IGF-I bioavailability. These functions are modulated by posttranslational modifications of IGFBPs such as proteolysis and phosphorylation. Levels of unbound bioavailable IGF-I have not previously been explored in muscle or other tissues.

This thesis focuses on IGF-I protein levels in the human skeletal muscle interstitial fluid. In models of endurance exercise in both sexes and in vitro, we explored factors expected to regulate local muscle IGF-I activity including circulating IGF-I and IGFBPs under the influence of interleukin-6 (IL-6) and sex hormones. This was possible by the development of a microdialysis approach. Unbound IGF-I in human skeletal muscle interstitial fluid was detected in microdialysate (md-IGF-I) collected from an intramuscular probe. Basal md-IGF-I at rest was in the same concentration range as free (unbound) IGF-I in serum and correlated with total (bound plus unbound) IGF-I. Endurance exercise with one leg (45 or 60 min), decreased md-IGF-I in the resting leg concomitantly with increased circulating IGFBP-1. This is the first evidence to support that increasing circulating IGFBP-1 decreases local muscle IGF-I bioavailability. Exercising leg md-IGF-I did not decrease and free IGF-I was released to the regional circulation (v-a difference) but with lack of correlation to systemic changes. We conclude that the regulation of unbound IGF-I in the exercising muscle is less affected by systemic factors than the resting muscle. Proteases partially cleave IGFBPs into distinct fragments and increase IGF bioavailability. This process may contribute to increased local IGF-I in exercising muscle. IGFBP-3 was cleaved during extended ultra endurance exercise (UEE). Since this may reflect local IGFBP-3 proteolysis we examined a Ca2+ - activated muscle protease m-calpain. In vitro, m-Calpain cleaved IGFBP-2 and -3 into fragments that we identified by N-terminal amino acid sequencing. Gonadal function was suppressed by UEE but with no major sex differences and no correlation to changes in IGF-IGFBP. For the first time, we demonstrated a net release of IL-6 from exercising muscle in women. The role of IL-6 was specifically addressed by a 3 h IL-6 infusion that increased IGFBP-1 concentrations with no effect on circulating free IGF-I or IGFBP-3.

The results from these studies shed new light on the regulation of skeletal muscle tissue IGF-I bioavailability which may be of importance for exercise adaptation and resting metabolism and anabolism.

List of scientific papers

I. U. Berg, J.K. Enqvist, C.M. Mattson, C. Carlsson-Skwirut, C.J. Sundberg, B. Ekblom, P. Bang (2006). "Lack of sex differences in the IGF-IGFBP response to ultra endurance exercise." (Submitted)

II. Berg U, Gustafsson T, Sundberg CJ, Carlsson-Skwirut C, Hall K, Jakeman P, Bang P (2006). "Local changes in the insulin-like growth factor system in human skeletal muscle assessed by microdialysis and arterio-venous differences technique." Growth Horm IGF Res 16(4): 217-23. Epub 2006 Aug 14
https://pubmed.ncbi.nlm.nih.gov/16904923

III. Berg U, Gustafsson T, Sundberg CJ, Kaijser L, Carlsson-Skwirut C, Bang P (2007). "Interstitial IGF-I in exercising skeletal muscle in women." Eur J Endocrinol 157(4): 427-435
https://pubmed.ncbi.nlm.nih.gov/17893256

IV. Pihl S, Carlsson-Skwirut C, Berg U, Ekström K, Bang P (2006). "Acute interleukin-6 infusion increases IGFBP-1 but has no short-term effect on IGFBP-3 proteolysis in healthy men." Horm Res 65(4): 177-84. Epub 2006 Mar 20
https://pubmed.ncbi.nlm.nih.gov/16549931

V. Berg U, Bang P, Carlsson-Skwirut C (2007). "Calpain proteolysis of insulin-like growth factor binding protein (IGFBP) -2 and -3, but not of IGFBP-1." Biol Chem 388(8): 859-63
https://pubmed.ncbi.nlm.nih.gov/17655506