Department of Biochemistry

Martin Adamo, Professor

Our laboratory studies insulin-like growth factor-I (IGF-I) synthesis and action throughout the life span. IGF-I is a 70 amino acid peptide synthesized primarily by the liver, which secretes this growth factor into the circulation. Most extra-hepatic tissues also synthesize IGF-I. Thus, IGF-I acts as both a circulating endocrine and autocrine/paracrine growth factor. IGF-I acts by binding to a heterotetrameric receptor with inherent tyrosine kinase activity. IGF-I binding stimulates the tyrosine kinase activity of the receptor resulting in a sequence of biochemical events that cause the activation of two major signaling kinases. One of these is the lipid kinase phosphatidylinositol 3-kinase (PI3K) and the other is the extracellular signal regulated kinase (ERK). Products of PI3K lead to the activation of a number of downstream kinases, most notably Akt/protein kinase B. ERK phosphorylates a variety of substrates. Collectively, these actions lead to increased cellular proliferation, survival, anabolism, and differentiated function.

IGF-I synthesis and secretion is highly regulated consistent with its important role in stimulating normal growth and metabolism, and mediating tissue maintenance and regeneration after damage. However, IGF-I also stimulates pathological growth processes such as fibrosis and cancer. Given these pleiotropic effects of IGF-I, it is not surprising that IGF-I has been implicated in the aging process. Reduction in IGF-I action leads to age-associated impairment of tissue function such as osteo- and sarcopenia. On the other hand, reductions in IGF-I action may actually reduce biological aging by decreasing cancer progression and by decreasing fibrotic and inflammatory pathways.

We utilize in vitro cell culture and in vivo animal models with manipulations of IGF-I and components of the IGF-I signaling pathway to determine the effects of IGF-I on the growth, differentiation, survival and metabolism of specific tissues, such as bone and skeletal muscle and in whole animals. For example, we are elucidating signaling pathways by which IGF-I mediates muscle survival during oxidative stress in vitro and in vivo. Results from these studies have demonstrated unique functions for the p110 alpha and p110 beta isoforms and for Akt isoforms in IGF-I survival and metabolic signaling in myogenic cells.

We are also elucidating how IGF-I and factors that regulate IGF-I expression determine differentiation along osteoblastic, myogenic and adipogenic lineages. These studies are being done in collaboration with experts in skeletal biology and mouse genetics at Maine Medical Research Center. Our studies indicate that the clock protein nocturnin, which acts to destabilize mRNAs, may promote adipogenic differentiation in part by inhibiting IGF-I expression, as well as through other effects on the adipogenic pathway.

A major translational goal of our work is to determine the effects of IGF-I signaling on stress response, metabolism, and life span in intact experimental animals. These studies utilize wild-type animals and animal models of genetically reduced serum and tissue IGF-I levels and of reduced levels of IGF-I receptors to determine how IGF-I action/signaling affects longevity, whole body and muscle response to oxidative stress, and insulin sensitivity. .

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