cAMP‐dependent protein kinase inhibits FoxO activity and regulates skeletal muscle plasticity in mice

Abstract

Although we have shown that catecholamines suppress the activity of the Ubiquitin‐Proteasome System (UPS) and atrophy‐related genes expression through a cAMP‐dependent manner in skeletal muscle from rodents, the underlying mechanisms remain unclear. Here, we report that a single injection of norepinephrine (NE; 1 mg kg−1; s.c) attenuated the fasting‐induced up‐regulation of FoxO‐target genes in tibialis anterior (TA) muscles by the stimulation of PKA/CREB and Akt/FoxO1 signaling pathways. In addition, muscle‐specific activation of PKA by the overexpression of PKA catalytic subunit (PKAcat) suppressed FoxO reporter activity induced by (1) a wild‐type; (2) a non‐phosphorylatable; (3) a non‐phosphorylatable and non‐acetylatable forms of FoxO1 and FoxO3; (4) downregulation of FoxO protein content, and probably by (5) PGC‐1α up‐regulation. Consistently, the overexpression of the PKAcat inhibitor (PKI) up‐regulated FoxO activity and the content of Atrogin‐1 and MuRF1, as well as induced muscle fiber atrophy, the latter effect being prevented by the overexpression of a dominant negative (d. n.) form of FoxO (d.n.FoxO). The sustained overexpression of PKAcat induced fiber‐type transition toward a smaller, slower, and more oxidative phenotype and improved muscle resistance to fatigue. Taken together, our data provide the first evidence that endogenous PKA activity is required to restrain the basal activity of FoxO and physiologically important to maintain skeletal muscle mass.

Study on the Correlation Between NF-κB and Central Fatigue

“…Some scholars used gene chip technology to screen the related genes of exercise-induced fatigue. They found that the up-regulated genes in quadriceps femoris of exercise-induced fatigue mice included PKA (Silveira et al 2020 ; Gordon et al 2017 ; Caiati et al 2013 ) and other protein kinase genes, which were involved in the occurrence and development of exercise-induced central fatigue (Gordon et al 2017 ). CREB (protein kinase A-cAMP response element-binding protein) is a transcription factor in the nucleus, which can regulate a variety of nervous system functions, such as learning and memory.…”

Suppression of FoxO1 mRNA by β2‐adrenoceptor–cAMP signaling through miR‐374b‐5p and miR‐7a‐1‐3p in C2C12 myotubes

“…As mentioned above, norepinephrine stimulation decreases FoxO1 protein abundance via the cAMP-PKA pathway in murine skeletal muscle [25]. b 2 -AR couples with the G protein, which activates adenylyl cyclase, catalyzing the formation of cAMP [37].…”

“…Recently, the injection of norepinephrine was shown to suppress FoxO transcriptional activity via the cAMP-protein kinase A (PKA) pathway, consequently decreasing the expression of Atrogin-1/MAFbx mRNA in murine skeletal muscles [23]. Interestingly, Silveria et al [25] also reported that norepinephrine stimulation induces FoxO1 phosphorylation and decreases FoxO1 protein abundance. The abundance of FoxO protein also has dramatic effects on its own transcriptional activity and/or the functions of its downstream targets [26,27].…”

Proteasome regulators in pancreatic cancer

“…FOXO transcription factors have a positive effect in proteasome regulation through activation of transcription of proteasome sub-units[ 12 ]. A pathophysiologic role of FOXO transcription factors in muscle atrophy through proteasome genes induction, and reversal of atrophy by protein kinase A inhibition of FOXO members FOXO1 and FOXO3 has been described[ 29 ]. Transcription co-activator Peroxisome Proliferator Activated Receptor gamma Co-activator 1alpha (PGC-1α) counteracts the atrophy promoting effects of FOXO3 and reduces denervation-induced muscle atrophy and cancer cachexia in mice[ 30 ].…”