CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation

Abstract

Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade; however, its role in skeletal muscle remains unknown. Here, we found that CaMKK2 expression levels were altered under physiological and pathological conditions including postnatal myogensis, freeze or cardiotoxin-induced muscle regeneration, and Duchenne muscular dystrophy. Overexpression of CaMKK2 suppressed C2C12 myoblast proliferation and differentiation, while inhibition of CaMKK2 had opposite effect. We also found that CaMKK2 is able to activate AMPK in C2C12 myocytes. Inhibition of AMPK could attenuate the effect of CaMKK2 overexpression, while AMPK agonist could abrogate the effect of CaMKK2 knockdown on C2C12 cell differentiation and proliferation. These results suggest that CaMKK2 functions as an AMPK kinase in muscle cells and AMPK mediates the effect of CaMKK2 on myoblast proliferation and differentiation. Our data also indicate that CaMKK2 might inhibit myoblast proliferation through AMPK-mediated cell cycle arrest by inducing cdc2-Tyr15 phosphorylation and repress differentiation through affecting PGC1α transcription. Lastly, we show that overexpressing CaMKK2 in the muscle of mice via electroporation impaired the muscle regeneration during freeze-induced injury, indicating that CaMKK2 could serve as a potential target to treat patients with muscle injury or myopathies. Together, our study reveals a new role for CaMKK2 as a negative regulator of myoblast differentiation and proliferation and sheds new light on the molecular regulation of muscle regeneration.

Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid

“…Depending on the cellular context and stimuli, CAMKK2 activation can exert either an inhibitory or stimulatory effect on cellular differentiation. In this regard, it has been shown that CAMKK2 activation inhibits myoblast [ 48 ] and preadipocyte differentiation [ 49 ], whereas it accelerates monocyte differentiation induced by colony stimulating factor 1 [ 50 ]. Our findings reveal that CAMKK2 suppresses granulocytic differentiation induced by ATRA.…”

The Role of AMPK in the Regulation of Skeletal Muscle Size, Hypertrophy, and Regeneration

“…A similar inhibitory effect of AICAR on primary bovine myoblasts was also observed [ 132 ]. Furthermore, transfection of C2C12 myoblasts with CamKKβ, an established AMPK activator, resulted in AMPK activation in myoblasts, cell cycle arrest and impaired proliferation as well as impaired subsequent differentiation, and this effect on proliferation and differentiation was AMPK-dependent since it was blocked by dominant-negative AMPK expression [ 133 ]. Together, these in vitro findings suggest that hyperactivation of AMPK in myoblasts blocks muscle proliferation and differentiation.…”

Dynamic changes of miRNAs in skeletal muscle development at New Zealand rabbits

“…In addition, novel_3 and novel_38 were the top 2 expressed novel DEmiRNAs, which targeted 12 and 110 genes, respectively. The target genes CaMKK2 [22], CD9 [23], BAG3 [24]and NUAK2 [25] of novel_3 are related to muscle regeneration. Target gene of novel_38 were not enriched in GO, but the target gene STAT5B was involved in the growth hormone and JAK-STAT signaling pathways, which were associated with skeletal muscle development [26,27].…”