Calcineurin signaling and PGC-1α expression are suppressed during muscle atrophy due to diabetes

Abstract

PGC-1α is a transcriptional coactivator that controls energy homeostasis through regulation of glucose and oxidative metabolism. Both PGC-1α expression and oxidative capacity are decreased in skeletal muscle of patients and animals undergoing atrophy, suggesting that PGC-1α participates in the regulation of muscle mass. PGC-1α gene expression is controlled by calcium- and cAMP-sensitive pathways. However, the mechanism regulating PGC-1α in skeletal muscle during atrophy remains unclear. Therefore, we examined the mechanism responsible for decreased PGC-1α expression using a rodent streptozotocin (STZ) model of chronic diabetes and atrophy. After 21d, the levels of PGC-1α protein and mRNA were decreased. We examined the activation state of CREB, a potent activator of PGC-1α transcription, and found that phospho-CREB was paradoxically high in muscle of STZ-rats, suggesting that the cAMP pathway was not involved in PGC-1α regulation. In contrast, expression of calcineurin (Cn), a calcium-dependent phosphatase, was suppressed in the same muscles. PGC-1α expression is regulated by two Cn substrates, MEF2 and NFATc. Therefore, we examined MEF2 and NFATc activity in muscles from STZ-rats. Target genes MRF4 and MCIP1.4 were both significantly reduced, consistent with reduced Cn signaling. Moreover, levels of MRF4, MCIP1.4, and PGC-1α were also decreased in muscles of CnAα-/- and CnAβ-/- mice without diabetes indicating that decreased Cn signaling, rather than changes in other calcium- or cAMP-sensitive pathways, were responsible for decreased PGC-1α expression. These findings demonstrate that Cn activity is a major determinant of PGC-1α expression in skeletal muscle during diabetes and possibly other conditions associated with loss of muscle mass.

miR-23a is decreased during muscle atrophy by a mechanism that includes calcineurin signaling and exosome-mediated export

“…Others have documented that NFAT increases miR-23a expression in cardiomyocytes and that Cn and NFATc3 increase miR-23a reporter gene activity (43). Consistent with our previous finding that Cn/ NFAT signaling is suppressed in muscle during STZ-induced diabetes (34), the level of miR-23a was decreased in diabetic rat muscle. In addition, pharmacological augmentation of Cn activity in C2C12 myotubes induced an increase in miR-23a that was blocked by CsA.…”

“…Previously, we demonstrated that Cn/NFAT signaling is suppressed in muscle during acute STZ-induced diabetes (34). Consistent with these observations, treatment of L6 myotubes with Dex (48 h) induced a decrease in the levels of RCAN1.4 mRNA (Fig.…”

“…We conclude that atrophy-inducing conditions downregulate miR-23a in muscle by mechanisms involving attenuated Cn/NFAT signaling and selective packaging into exosomes. atrophy; skeletal muscle; glucocorticoids; calcineurin; microRNA; gene expression SKELETAL MUSCLE ATROPHY is a frequent consequence of catabolic conditions (e.g., mechanical ventilation, diabetes, chronic kidney disease, and glucocorticoid-induced insulin resistance) that decreases the quality of life for patients and increases their risk of mortality (13,15,25,34). Muscle atrophy typically results from a coordinated program of changes in gene and protein expression that leads to increased activity of intracellular proteolytic systems, including the ubiquitin-proteasome pathway and autophagy (19,20,37).…”

Exercise training has beneficial anti-atrophy effects by inhibiting oxidative stress-induced MuRF1 upregulation in rats with diabetes

“…Collectively, our results provide further support for the concept that oxidative stress stimulates the loss of muscle protein by upregulating the ubiquitin proteasome pathway in the setting of diabetes. However, other factors, including heat shock proteins, caspases, atrogin-1, FOXO and PGC-1α, also play important roles in mediating oxidative stress signaling to regulate muscle atrophy (Gwag et al, 2009;Roberts-Wilson et al, 2010). Further studies to address the functional interaction of these factors with MuRF1 will provide more insight into the molecular mechanisms underlying oxidative-stress-induced muscle atrophy.…”

Depressed mitochondrial biogenesis and dynamic remodeling in mouse tibialis anterior and gastrocnemius induced by 4‐week hindlimb unloading

“…And, it can also be post-translationally modificated by silent mating type information regulation 2 homolog 1 (SIRT1) and AMP-activated protein kinase (AMPK) (10). Mitochondrial biogenesis disruption was found in many kinds of atrophy models (11). After short time unloading (24 h), the PGC-1a, b, and PPARa were all reduced in both soleus and gastrocnemius (GAS) muscle, suggesting that mitochondrial biogenesis is disrupted in the very early stage of the unloading (12).…”