Characterization of skeletal muscle satellite cells metabolism and redox balance: role of aldehydes as metabolic sensors

Abstract

Skeletal muscle satellite cells are stem cells located between basal lamina and the sarcolemma of the muscle fiber. Once activated, these mononuclear progenitor cells are capable of triggering a cellular reprogramming resulting in proliferation, renewal and differentiation of these cells in myoblasts. Considering the different energetic demands of the processes described above, the metabolic state of these satellite cells may be synchronized with their functional need. However, it is important to note that the metabolic profile of the skeletal muscle satellite cells in different states of activation has not been described yet. Moreover, it is unknown whether possible changes in metabolism and consequent reorganization of redox signaling are essential in modulating the state of skeletal muscle satellite cells. Therefore, in this proposal we intent to: 1. Isolate and culture skeletal muscle satellite cells of wild type mice; and 2. Characterize energetic metabolism and redox balance of this population of satellite cells at different states of activation. Once characterized the bioenergetics profile of skeletal muscle satellite cells, we intend to pursue possible cellular signal coming from energetic metabolism and redox balance (metabolic signaling) involved in the control of skeletal muscle satellite cells biology. The short-chain aldehydes (stable and extremely reactive molecules) are considered important metabolic products and interlocutors between energetic metabolism/oxidative stress and different cellular processes (e.g. protein degradation and mitochondrial dynamics). Currently, it is known that aldehydes derived from glycolytic (acetaldehyde) and oxidative (4-hydroxy-2-nonenal) metabolisms directly affect the biology of mesenchymal stem cells. However, it is unknown the contribution of these adehydes in the biology of skeletal muscle satellite cells. Thus, the second aim of this project will be assessing whether the aldehydes-mediated metabolic signaling (acetaldehyde and 4-hydroxy-2-nonenal) is essential or secondary to the skeletal muscle satellite cells biology. For this we will use both pharmacological and genetic interventions able to block or stimulate aldehydes metabolism through the mitochondrial enzyme aldehyde dehydrogenase 2. These experiments will be performed on systems with different degree of complexity (in vivo, ex vivo, isolated fiber and cell culture). Finally, skeletal muscle satellite cells will be isolated from wild-type and transgenic aldehyde dehydorgenase 2 mice (that present impaired aldehyde metabolism), transplanted in an experimental model of metabolic stress-induced muscle damage (permanent ligation of the femoral artery in mice), and we will evaluate the ability of muscle regeneration. Our preliminary results show decreased aldehyde dehydrogenase 2 activity, aldehyde accumulation, muscle injury and loss of contractile function in the aforementioned experimental model. FInally, this project will first describe the satellite cell energetic metabolism/redox balance in its different states of activation. Furthermore, we will characterize the role of aldehydes as a possible interlocutors between energetic metabolism and skeletal muscle satellite cells activation (metabolic signaling), as well as their participation in the process of muscle regeneration. Our results will open a new perspective in the development of tools that regulate the biology of satellite cells. (AU)