Prdx6 Plays a Main Role in the Crosstalk between Aging and Metabolic Sarcopenia

Abstract

With the increase in average life expectancy, several individuals are affected by age-associated non-communicable chronic diseases (NCDs). The presence of NCDs, such as type 2 diabetes mellitus (T2DM), leads to the reduction in skeletal muscle mass, a pathological condition defined as sarcopenia. A key factor linking sarcopenia with cellular senescence and diabetes mellitus (DM) is oxidative stress. We previously reported as the absence of Peroxiredoxin 6 (Prdx6), an antioxidant enzyme implicated in maintaining intracellular redox homeostasis, induces an early-stage of T2DM. In the present study we sought to understand the role of Prdx6 in the crosstalk between aging and diabetic sarcopenia, by using Prdx6 knockout (Prdx6-/-) mice. Absence of Prdx6 reduced telomeres length and Sirtuin1 (SIRT1) nuclear localization. An increase in Sa-β-Gal activity and p53-p21 pro-aging pathway were also evident. An impairment in IGF-1 (Insulin-like Groth Factor-1)/Akt-1/mTOR pathway leading to a relative increase in Forkhead Box O1 (FOXO1) nuclear localization and in a decrease of muscle differentiation as per lower levels of myoblast determination protein 1 (MyoD) was observed. Muscle atrophy was also present in Prdx6-/- mice by the increase in Muscle RING finger 1 (MuRF1) levels and proteins ubiquitination associated to a reduction in muscle strength. The present study, innovatively, highlights a fundamental role of Prdx6, in the crosstalk between aging, sarcopenia, and DM.

Redox Signaling and Sarcopenia: Searching for the Primary Suspect

“…Prxs have been shown to mediate the oxidative signal from H 2 O 2 to target transcription factors such as PPARγ and NF-κB [187]. Overexpression of Prx3 was shown to abolish myocyte atrophy, loss of contractile force, and ROS production in a SOD-1 KO mouse model [193], whereas Prx6 KO has been shown to induce muscle atrophy via an increase in MuRF1, a primary mediator of ubiquitin proteolysis [194]. Furthermore, Prx3 is heavily involved in ameliorating mitochondrial homeostasis and muscle contractile function [195].…”

Elephant seal muscle cells adapt to sustained glucocorticoid exposure by shifting their metabolic phenotype

“…Our results also show that besides suppressing mitochondrial metabolism, DDIT4 regulates prdx6 expression. Prdx6 supports muscle function (103,104) by limiting lipid peroxidation (105,106) and promoting myogenesis (107). Growing evidence shows that DDIT4 regulates redox homeostasis, but its specific role in oxidant generation or removal remains unclear.…”

Elephant seal muscle cells adapt to sustained glucocorticoid exposure by shifting their metabolic phenotype

“…Our results also show that besides suppressing mitochondrial metabolism, DDIT4 regulates prdx6 expression. Prdx6 supports muscle function (Pacifici et al, 2020; Sakellariou et al, 2018) by limiting lipid peroxidation (Arevalo & Vázquez-Medina, 2018; Fisher et al, 2018). Growing evidence shows that DDIT4 regulates redox homeostasis, but its specific role in oxidant generation or removal remains unclear.…”