Abstract
In several cell types, the protein deacetylase SIRT1 regulates the activities of FoxO transcription factors whose activation is critical in muscle atrophy. However, the possible effects of SIRT1 on the activity of FoxOs in skeletal muscle and on the regulation of muscle size have not been investigated. Here, we show that after food deprivation, SIRT1 levels fall dramatically in type II skeletal muscles (tibialis anterior), which show marked atrophy, unlike in the liver (where SIRT1 rises) or heart or the soleus, a type I muscle (where SIRT1 is unchanged). Maintenance of high SIRT1 levels by electroporation in mouse muscle inhibits markedly the muscle wasting induced by fasting as well as by denervation, and these protective effects require its deacetylase activity. SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3. It thus prevents the induction of key atrogenes, including the muscle-specific ubiquitin ligases, atrogin1 and MuRF1, and multiple autophagy (Atg) genes and the increase in overall proteolysis. In normal muscle, SIRT1 overexpression by electroporation causes rapid fiber hypertrophy without, surprisingly, activation of the PI3K-AKT signaling pathway. Thus, SIRT1 activation favors postnatal muscle growth, and its fall appears to be critical for atrophy during fasting. Consequently, SIRT1 activation represents an attractive possible pharmacological approach to prevent muscle wasting and cachexia.
Highlights
SIRT1 regulates the activity of FoxO transcription factors and protects tissues from diverse insults
SIRT1 Content Decreases during Fasting When Atrogenes Are Induced—To determine whether SIRT1 is involved in muscle atrophy during fasting for different periods, we analyzed the expression of SIRT1 and two atrophy-associated ubiquitin ligases, atrogin1 and MuRF1, in mouse tibialis anterior (TA)2 muscles
Expression of all three was up-regulated upon fasting, as reported previously [5], but SIRT1 overexpression prevented their induction (Fig. 2E). This inhibition of autophagy gene induction required the deacetylase activity of SIRT1 (Fig. 2E) and, together with the inhibition of atrogin1 and MuRF1, seems to account for the blockage of muscle wasting in the fasted animals. Because all these atrogenes are FoxO3 targets [4, 5, 8], these findings indicate that SIRT1 overexpression prevents FoxO3 activation upon fasting
Summary
SIRT1 regulates the activity of FoxO transcription factors and protects tissues from diverse insults. SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 It prevents the induction of key atrogenes, including the muscle-specific ubiquitin ligases, atrogin and MuRF1, and multiple autophagy (Atg) genes and the increase in overall proteolysis. Types of muscle wasting, induced by diverse physiological stimuli, involve similar adaptive changes in the transcription of a common set of atrophy-related genes (atrogenes) These adaptations lead to a general activation of protein degradation through the ubiquitin proteasome pathway [3], as well as increased autophagy [3,4,5]. We show here that SIRT1 overexpression, by inhibiting FoxO1 and 3, is a major regulator of muscle mass, and can prevent the rapid loss of muscle mass upon fasting or denervation, and can induce rapid hypertrophy of normal muscle
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