Abstract
Mammalian skeletal muscle (SkM) tissue engages the Nrf2-Keap1-dependent antioxidant defense mechanism to respond adaptively to stress. Redox homeostasis mediated by the reversible modification of selective cysteines is the prevalent mode of regulation. The protein targets of SkM redox regulation are largely unknown. We previously reported the proteomic profiles of soleus (Sol) and extensor digitorum longus (EDL) with Nrf2 or Keap1 gene deletion, using SkM-specific Nrf2 or Keap1 knockout models; iMS-Nrf2flox/flox; and iMS-Keap1flox/flox. Here, we employed these two animal models to understand the global expression profile of red tibialis anterior (RTA) using a label free approach and its redox proteomics using iodoacetyl tandem mass tag (iodoTMTTM)-labeled cysteine quantitation. We quantified 298 proteins that were significantly altered globally in the RTA with Nrf2 deficiency but only 21 proteins in the Keap1 KO samples. These proteins are involved in four intracellular signaling pathways: sirtuin signaling, Nrf2 mediated oxidative stress response, oxidative phosphorylation, and mitochondrion dysfunction. Moreover, we identified and quantified the cysteine redox peptides of 34 proteins, which are associated with mitochondrial oxidative phosphorylation, energy metabolism, and extracellular matrix. Our findings suggest that Nrf2-deficient RTA is implicated in metabolic myopathy, mitochondrial disorders, and motor dysfunction, possibly due to an enhanced oxidative modification of the structure and functional proteins in skeletal myocytes.
Highlights
Skeletal muscle in mammals is tightly regulated under stress conditions and dysfunctional physiological processes
Employing proteomics and bioinformatics analyses of skeletal muscle (SkM) with Nrf2- or Keap1- deficiency, we identified over 200 proteins governed by Nrf2 that are involved in antioxidant defense, mitochondrial function, oxidoreduction coenzyme metabolism, cellular detoxification, and many other key biology processes [4]
We investigated the effects of Nrf2- or Keap1-deletion on the proteomic profile of red tibialis anterior (RTA), a muscle composed of Type IIX
Summary
Skeletal muscle in mammals is tightly regulated under stress conditions and dysfunctional physiological processes. The Nrf2-Keap system is one of the most efficient antioxidant defenses that is active in muscle tissues in response to reactive oxygen species (ROS) and related species that have a damaging effect on skeletal myocytes. In oxidative stress, when reactive oxygen species (ROS) increases, Nrf escapes from Keap and translocates to the nucleus, upregulating a large group of antioxidant-associated proteins to restore redox balance. It has been well-recognized that Nrf plays a critical role in protecting skeletal muscle (SkM) function, during exercise, when contracting SkM generates a large amount of reactive oxygen species (ROS) [1].
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