Quantitative Proteomics Identifies Novel Nrf2-Mediated Adaptative Signaling Pathways in Skeletal Muscle Following Exercise Training

Anjali Bhat; Rafay Abu; Sankarasubramanian Jagadesan; Neetha Nanoth Vellichirammal; Ved Vasishtha Pendyala; Li Yu; Tara L Rudebush; Chittibabu Guda; Irving H Zucker; Vikas Kumar; Lie Gao

doi:10.3390/antiox12010151

Quantitative Proteomics Identifies Novel Nrf2-Mediated Adaptative Signaling Pathways in Skeletal Muscle Following Exercise Training

Antioxidants (Basel). 2023 Jan 9;12(1):151. doi: 10.3390/antiox12010151.

Authors

Anjali Bhat¹, Rafay Abu^{2

3}, Sankarasubramanian Jagadesan⁴, Neetha Nanoth Vellichirammal⁴, Ved Vasishtha Pendyala¹, Li Yu⁵, Tara L Rudebush⁵, Chittibabu Guda⁴, Irving H Zucker⁵, Vikas Kumar^{2

4}, Lie Gao¹

Affiliations

¹ Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
² Mass Spectrometry and Proteomics Core Facility, University of Nebraska Medical Center, Omaha, NE 68198, USA.
³ Department of Biochemistry, Glocal University, Saharanpur 247121, Uttar Pradesh, India.
⁴ Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁵ Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Abstract

Exercise training (ExT) improves skeletal muscle health via multiple adaptative pathways. Nrf2 is a principal antioxidant transcription factor responsible for maintaining intracellular redox homeostasis. In this study, we hypothesized that Nrf2 is essential for adaptative responses to ExT and thus beneficial for muscle. Experiments were carried out on male wild type (WT) and iMS-Nrf2^flox/flox inducible muscle-specific Nrf2 (KO) mice, which were randomly assigned to serve as sedentary controls (Sed) or underwent 3 weeks of treadmill ExT thus generating four groups: WT-Sed, WT-ExT, KO-Sed, and KO-ExT groups. Mice were examined for exercise performance and in situ tibialis anterior (TA) contractility, followed by mass spectrometry-based proteomics and bioinformatics to identify differentially expressed proteins and signaling pathways. We found that maximal running distance was significantly longer in the WT-ExT group compared to the WT-Sed group, whereas this capacity was impaired in KO-ExT mice. Force generation and fatigue tolerance of the TA were enhanced in WT-ExT, but reduced in KO-ExT, compared to Sed controls. Proteomic analysis further revealed that ExT upregulated 576 proteins in WT but downregulated 207 proteins in KO mice. These proteins represent pathways in redox homeostasis, mitochondrial respiration, and proteomic adaptation of muscle to ExT. In summary, our data suggest a critical role of Nrf2 in the beneficial effects of SkM and adaptation to ExT.

Keywords: Nrf2; exercise; proteomics; skeletal muscle.

Abstract

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