Abstract
Glucose restriction (GR) impairs muscle cell differentiation and evokes myotube atrophy. Resveratrol treatment in skeletal muscle cells improves inflammatory-induced reductions in skeletal muscle cell differentiation. We therefore hypothesised that resveratrol treatment would improve muscle cell differentiation and myotube hypertrophy in differentiating C2C12 myoblasts and mature myotubes during GR. Glucose restriction at 0.6 g/L (3.3 mM) blocked differentiation and myotube hypertrophy versus high-glucose (4.5 g/L or 25 mM) differentiation media (DM) conditions universally used for myoblast culture. Resveratrol (10 µM) treatment increased SIRT1 phosphorylation in DM conditions, yet did not improve differentiation when administered to differentiating myoblasts in GR conditions. Resveratrol did evoke increases in hypertrophy of mature myotubes under DM conditions with corresponding elevated Igf-I and Myhc7 gene expression, coding for the ‘slow’ type I MYHC protein isoform. Inhibition of SIRT1 via EX-527 administration (100 nM) also reduced myotube diameter and area in DM conditions and resulted in lower gene expression of Myhc 1, 2 and 4 coding for ‘intermediate’ and ‘faster’ IIx, IIa and IIb protein isoforms, respectively. Resveratrol treatment did not appear to modulate phosphorylation of energy-sensing protein AMPK or protein translation initiator P70S6K. Importantly, in mature myotubes, resveratrol treatment was able to ameliorate reduced myotube growth in GR conditions over an acute 24-h period, but not over 48–72 h. Overall, resveratrol evoked myotube hypertrophy in DM conditions while favouring ‘slower’ Myhc gene expression and acutely ameliorated impaired myotube growth observed during glucose restriction.
Highlights
Calorie Restriction (CR) promotes improvements in lifespan and healthspan in mammalian organisms due to chronic reductions in Insulin/Insulin-like-Growth-Factor-I (IGF-I) signalling, inflammation, DNA damage and oxidative stress
In order to first assess the optimal dose of resveratrol and EX-527 in C2C12 cells, SIRT1 phosphorylation was assessed in differentiation media (DM) control glucose conditions
The higher dose of 15 μM resveratrol showed no additional increase versus 10 μM and higher doses of 30 and 60 μM of resveratrol were cytotoxic and evoked cell death as suggested in previous independent studies using these doses in C2C12 cells [33]
Summary
Calorie Restriction (CR) promotes improvements in lifespan and healthspan in mammalian organisms due to chronic reductions in Insulin/Insulin-like-Growth-Factor-I (IGF-I) signalling, inflammation, DNA damage and oxidative stress (reviewed in [1]). During CR a paradox exists where an attempt by the organism to improve longevity via reductions in IGF signalling are potentially at the expense of a loss in skeletal muscle regenerative capacity and mass (reviewed in [1]). As a consequence, using pharmacological or naturally derived agents that maintain muscle while calorie restricted would potentially be advantageous to improve health/lifespan while reducing the loss of muscle mass. Research into the activation of the Sirtuins (SIRT17), a group of protein deacetylases involved in the process of chromatin remodelling and gene regulation (see [13], by a naturally occurring polyphenol resveratrol (contained in the skin of red grapes), has provided some insights into the Sirtuins’ potential in both enabling improved healthspan and maintaining muscle cell regenerative function
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