Hypertrophy of Rat Skeletal Muscle Is Associated with Increased SIRT1/Akt/mTOR/S6 and Suppressed Sestrin2/SIRT3/FOXO1 Levels

Abstract

Despite the intensive investigation of the molecular mechanism of skeletal muscle hypertrophy, the underlying signaling processes are not completely understood. Therefore, we used an overload model, in which the main synergist muscles (gastrocnemius, soleus) of the plantaris muscle were surgically removed, to cause a significant overload in the remaining plantaris muscle of 8-month-old Wistar male rats. SIRT1-associated pro-anabolic, pro-catabolic molecular signaling pathways, NAD and H2S levels of this overload-induced hypertrophy were studied. Fourteen days of overload resulted in a significant 43% (p < 0.01) increase in the mass of plantaris muscle compared to sham operated animals. Cystathionine-β-synthase (CBS) activities and bioavailable H2S levels were not modified by overload. On the other hand, overload-induced hypertrophy of skeletal muscle was associated with increased SIRT1 (p < 0.01), Akt (p < 0.01), mTOR, S6 (p < 0.01) and suppressed sestrin 2 levels (p < 0.01), which are mostly responsible for anabolic signaling. Decreased FOXO1 and SIRT3 signaling (p < 0.01) suggest downregulation of protein breakdown and mitophagy. Decreased levels of NAD+, sestrin2, OGG1 (p < 0.01) indicate that the redox milieu of skeletal muscle after 14 days of overloading is reduced. The present investigation revealed novel cellular interactions that regulate anabolic and catabolic processes in the hypertrophy of skeletal muscle.

Unlocking the Nexus of Sirtuins: A Comprehensive Review of Their Role in Skeletal Muscle Metabolism, Development, and Disorders

“…Sirtuins, particularly SIRT1 and SIRT6, play significant roles in this process (Table 3 ). Research indicates that overload-induced hypertrophy in skeletal muscles of rats is linked to increased expression of SIRT1 but decreased SIRT3 level, which is implicated in mitochondrial degradation 122 , 123 . SIRT1 also regulates myonuclear domain size in skeletal muscle fibers, where overexpression decreases domain size while inactivation increases it, with no significant impact on muscle force 124 .…”

The Pathogenesis of Diabetes

“…Liu et al found that iris reduced gluconeogenesis by downregulating PI3K/Akt/Foxo1-mediated PEPCK and G6Pase compared with the model group, thereby improving glucose homeostasis in STZ/HFD mice [ 122 ]. Foxo1 also contributes to the regulation of glucose in skeletal muscle [ 130 ]. Under the condition of chronic starvation, increased foxo1 expression in muscle binds to the promoter of pyruvate dehydrogenase kinase-4 gene, resulting in the conversion of pyruvate to acetyl-CoA and accelerating glucose consumption [ 131 ].…”

FoxO1 as a tissue-specific therapeutic target for type 2 diabetes

“…One mechanism through which SIRT1 improves T2D symptoms is by deacetylating and thus activating FoxO1 in adipocytes and increasing FoxO1’s interaction with its coactivator CCAAT/enhancer-binding protein α (C/EBPα) to upregulate the transcription of the insulin-sensitizing hormone adiponectin ( 59 ). However, SIRT1 can also act to mitigate T2D by enhancing AKT-mediated FoxO1 inactivation in tissues like liver and skeletal muscle ( 60 , 61 ). Therefore, increased SIRT1 can improve T2D symptoms by either activating or inactivation FoxO1.…”

“…Further studies suggest that both AKT and SIRT1 regulate FoxO1’s effects on muscle mass and GLUT4 ( 107 ). Elevated SIRT1 during cardiac or skeletal muscle hypertrophy has been associated with increased AKT levels and activity and decreased FoxO1 ( 61 , 107 – 109 ). For example, Gombos et al.…”