Research Article: An autoregulatory loop reverts the mechanosensitive Sirt1 induction by EGR1 in skeletal muscle cells

Date Published: July 18, 2012

Publisher: Impact Journals LLC

Author(s): Patricia S. Pardo, Aladin M. Boriek.

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Abstract

Muscle contraction is associated with the production of reactive oxygen species (ROS). Mechanisms of ROS scavenging are fundamental to avoid muscle damage. We had previously discovered a stretch-induced genetic program in myotubes that triggers an antioxidant defense. At the core of this mechanism, transcriptional activation of SIRT1 by the early growth response protein EGR1 results in increased MnSOD activity through the activation of Sod2 by SIRT1/FOXO pathway. In this report, we show experimental evidence that; a) EGR1 and SIRT1 proteins physically interact at the time of maximal Sirt1 induction, b) SIRT1 has a negative effect on the activation of the Sirt1 promoter by EGR1. Thus, the interaction between EGR1 and SIRT1 describes an autoregulatory loop that shuts down the stretch-induced Sirt1 expression.

Partial Text

SIRT1 (sirtuin 1) is a protein deacetylases that uses NAD+ as a cofactor in such a way that their activity is modulated by redox status. In skeletal muscle cells, SIRT1 activity plays important roles in differentiation and adaptations to nutrient availability and exercise [reviewed in 1]. Several lines of evidence have shown that SIRT1 plays a major role in mechanisms of antioxidant defense in several tissues [2-5]. Contraction associated ROS production results in cumulative oxidative stress in skeletal muscles [6]. Recent findings from our group implicated EGR1 and SIRT1 in a mechanical stretch-induced mechanism that contributes to ROS detoxification. In particular, a fast induction of the Sirt1 gene occurs in myotubes in response to mechanical stretch [7]. The up-regulation of SIRT1 expression by stretch occurs at the transcriptional level and requires the binding of the early growth response protein, EGR1 to the Sirt1 promoter. The stretch-dependent induction of Sirt1, leads to SIRT1-dependent FOXO4 deacetylation and increased expression of its target, the Mn-dependent superoxidase dismutase gene, Sod2 [7, 8]. This stretch-induced gene activation program contributes in the removal of the excess of reactive oxygen species, ROS, generated by the mechanical stimulus and serves to prevent long exposure to ROS levels that might result in cell damage.

Muscle contraction increases generation of ROS under physiological conditions and has been associated with diminished contractile function and fatigue during exercise [12]. In the long term, ROS production leads to cell damage: increased oxidative stress due to altered redox status is a hallmark of skeletal muscle aging [1, 5, 13]. Thus, a better understanding of the mechanisms controlling anti-oxidative defense in skeletal muscle cells in response to mechanical stimuli may help to define proper interventions to prevent the deleterious effects of oxidative stress on muscle function at old ages.

 

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