The mental cadmium and the metalloid arsenic (collectively referred to as toxic metals, TM) are important environmental pollutants causing known human health problems. Among the affected organs and tissues are muscles. E.g. one of the critical target of the cadmium toxicity is the vascular smooth musculature resulting in sustained contraction with systemic consequences like hypertension. At molecular levels, the impact of TMs on muscles is only poorly understood. Identified cellular changes involve stimulated signal transduction cascades including the MAP kinases, Erk and p38, and profound rearrangements (fragmentation) of the actin filaments. In recent years, the so-called small heat shock proteins (sHSPs) of mammals were reported to be involved in the cellular response to TMs, including both elevated abundance and degree of phosphorylation. At the same time, sHSPs were identified to play an important role in function and protection of striated and smooth muscles. The long-term objective of this project is to investigate and understand the involvement if sHSPs in mediating the detrimental effects of TMs in muscles. It is hypothesized that the muscle toxicity of TMs is mediated in part by the action of sHSPs resulting in complex changes in interactions. Of sHSPs with each other and with other sHSPs in muscle. It will be investigated how the interaction of sHSPs with themselves and with the actin filaments is regulated in muscles, and how TMs interfere. According to the specific aims, the goals of this project are: 1) To determine in muscle i) the effect of TMs on the amount, phosphorylation and complkex-forming properties of sHSPs, and ii) the specific serines and/or threonines of each sHsp phosphorylated in response to TM treatment; 2. To analyze using genetic and in vitro biochemical assays the interaction between these sHSPs and the effect of TM- caused phosphorylation on these interactions; 3) To analyze in vitro and in vivo i) the regulation of muscle microfilament assembly and organization by sHSPs; and ii) the effects of TM-caused phosphorylation of sHSPs on actin filament assembly and organization; and 4) To identify and study other muscle proteins interacting specifically with HSP22, and the impact of TMs on this interaction.
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