Abstract
This study aims to explore the impact of nuclear factor erythroid 2-related factor 2 (Nrf2) deficiency on skeletal muscle autophagy and the development of sarcopenia. LC3b, P62, Bnip3, Lamp-1, and AMPK protein levels were measured in muscle from young, middle-aged, old Nrf2−/− (knockout, KO) mice and age-matched wild-type (WT) C57/BL6 mice. Autophagy flux was measured in young WT, young KO, old WT, old KO mice, using colchicine as autophagy inhibitor. There was a trend of higher accumulation of LC3b-II, P62, Bnip3, Lamp-1 induced by colchicine in old WT mice compared with young WT mice. Colchicine induced a significantly higher accumulation of LC3b-II, P62, Bnip3, Lamp-1 in KO mice compared with WT mice, both in the young and old groups. AMPK and reactive oxygen species (ROS) were unregulated following Nrf2 KO and increasing age, which was consistent with the increasing trend of autophagy flux following Nrf2 KO and increasing age. Nrf2 KO and increasing age caused decreased cross-sectional area of extensor digitorum longus and soleus muscles. We concluded that Nrf2 deficiency and increasing age may activate AMPK and ROS signals to cause excessive autophagy activation in skeletal muscle, which can be a potential mechanism for the development of sarcopenia.
Highlights
Autophagy is an evolutionary conserved housekeeping cellular degradation and recycling process, whereby misfolded proteins and exhausted organelles are degraded to maintain cellular homeostasis
Most of these evidences were based on measurements of autophagy-related genes/proteins at. the static level, which can often lead to discrepancies in interpretation
It is has been recognized that autophagy flux measurements can provide direct evidence of the dynamic process of autophagy
Summary
Autophagy is an evolutionary conserved housekeeping cellular degradation and recycling process, whereby misfolded proteins and exhausted organelles are degraded to maintain cellular homeostasis. Skeletal muscle is the most abundant tissue in human body, accounting for about 40-55% of the body weight. It is the largest metabolic organ in the body [1]. Deficiency in the basic autophagy function causes accumulation of misfolded proteins and exhausted organelles and results in skeletal muscle cell dysfunction and death. Excessive autophagy can be deleterious by causing cellular stress and muscle protein degradation [4]
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