What is CREB and how is it activated?
CREB (cAMP Response Element–Binding protein, typically CREB1) is a transcription factor of the bZIP family that recognizes CRE elements (TGACGTCA) in the promoters/enhancers of numerous genes. Its activity depends primarily on the phosphorylation of Ser133 (by PKA, CaMKIV, MSK/p38, etc.), which allows the recruitment of the coactivators CBP/p300. A second level of control is mediated by CRTC coactivators (Crtc1/2/3, formerly TORC), whose nuclear translocation is regulated by the protein kinase SIK and Ca2⁺-dependent phosphatases (calcineurin, PP2A). When CRTCs enter the nucleus, they markedly enhance CREB-dependent transcription. This CREB–CRTC axis is particularly relevant in muscle.
Skeletal muscle: metabolism, plasticity and performance
Oxidative Programs and PGC-1α.
A key target of CREB in muscle is PPARGC1A (PGC-1α), a coactivator that governs mitochondrial biogenesis and the oxidative phenotype. The PPARGC1A promoter contains conserved CRE sites; cAMP and Ca2⁺-dependent stimuli (PKA/CaMKIV) increase PGC-1α via CREB, promoting oxidative metabolism, fatigue resistance, and exercise adaptations. β-agonists, catecholamines, and intense exercise activate the CRTC/CREB axis, increasing pro-metabolic and anabolic genes. Muscle-specific activation of CRTC2 (CREB1 coactivator) in mouse models improves energy expenditure, preserves lean mass during fasting, and counteracts the catabolic effects of glucocorticoids. These data directly link the Crtc2/Creb1 axis to the maintenance of metabolic and muscle function.
Muscle fiber remodeling
CREB regulates nuclear receptors of the NR4A family (Nr4a1/Nur77, Nr4a3/NOR1), key players in mitochondrial oxidation. More recently, a PROKR1–CREB–NR4A2 axis has been identified that promotes the specification of oxidative fibers and mitochondrial biogenesis, providing a further link between hormonal signals and phenotypic remodeling. The deacetylase Sirt6 modulates CREB and represses Sox6, promoting a shift toward slow-oxidative fibers with improved performance; the Sirt6–CREB axis has been proposed as a potential “exercise-mimetic” target. Crtc/Creb activation stimulates an anabolic program that, via PGC-1α4/IGF-1/Akt1, supports muscle growth and performance. It is the molecular basis of part of the strength-promoting effects induced by catecholamines and high-intensity exercise.
Myogenesis and regeneration: role in satellite cells
CREB is not just “metabolic”: in quiescent satellite cells, it establishes the proliferative competence required for expansion and self-renewal after injury. Inhibiting CREB in satellite cells impairs exit from quiescence and regeneration, through a CREB–MPP7–AMOT–YAP1 regulatory axis that governs the nuclear accumulation of YAP1 and the proliferative state. Furthermore, activated CREB after acute injury promotes myoblast proliferation and regeneration in vivo (including in dystrophinopathy models).
Glucocorticoids and muscle atrophy
In glucocorticoid-induced atrophy, a reduction in PGC-1α and an alteration in nuclear trafficking of CRTC are observed, with an increase in SIK and a reduction in calcineurin. Under these conditions, CREB/CRTC signaling is attenuated, although CREB can be phosphorylated, contributing to the loss of the oxidative program and the induction of atrogens (MuRF1, Atrogin-1). This axis explains why strategies that reactivate CREB/CRTC could protect against wasting in chronic and cachectic diseases.
Cardiac muscle: excitability, energy and remodeling
In cardiomyocytes, CREB transduces β-adrenergic/cAMP signals and directly influences the shape and duration of the action potential, with implications for ion channel remodeling in conditions of altered cAMP (e.g., heart failure). Cardiomyocyte inactivation of CREB or the expression of dominant-negative forms causes contractile dysfunction, mitochondrial alterations (density, ultrastructure, ROS) and high mortality (more marked in females), underlining a role for CREB in cardiac bioenergetics and adaptive responses to exercise.
Integrated framework and therapeutic perspectives
Overall, CREB integrates neurohumoral (β-adrenergic), metabolic (cAMP, Ca²⁺), mechanical, and epigenetic (Sirt6) signals to coordinate: (i) fiber identity and plasticity (toward oxidative phenotypes), (ii) mitochondrial efficiency and fatigue resistance, (iii) anabolic growth, and (iv) post-injury regenerative capacity. Dysfunction of the CREB/CRTC axis contributes to secondary sarcopenia, glucocorticoid atrophy, and, in the heart, electrical/mitochondrial dysfunction. At the translational level, selective activation of CRTC or upstream pathways (SIK inhibitors, calcineurin modulation) and the Sirt6–CREB axis are emerging as targets to mimic the benefits of exercise or protect against catabolism; however, efficacy and safety data in humans remain preliminary.
CREB and bone tissue function
CREB is typically “switched on” by phosphorylation on Ser133 by PKA, CaMKIV, ERK/RSK and other kinases. Phosphorylation promotes the recruitment of coactivators: these modules (CREB–CBP/p300–CRTC) are also central to bone homeostasis. The PTH receptor (PTH1R), expressed in cells of the osteoblastic lineage (including osteocytes), is a potent activator of the cAMP/PKA/CREB pathway. Pulsatile activation of the receptor initiates early (seconds/minutes) cAMP/PKA/CREB events that then propagate toward osteoanabolic and remodeling gene programs.
The Role of CREB in osteoblasts
In osteoblasts, CREB induces immediate-response genes such as c-fos and controls osteoblast-specific promoters (e.g., osteocalcin and bone sialoprotein or BSP), contributing to maturation and function. Furthermore, it promotes bone morphogenetic protein 2 or BMP2 (via a functional CRE in the promoter), coordinating the synergistic PTH-BMP cross-talk. It also regulates MMP13 (collagenase-3) in remodeling responses. Stimuli such as fluid shear stress activate Ca2+/ERK pathways, culminating in CREB phosphorylation/activation and induction of genes such as FosB/ΔFosB; CREB is therefore also an effector of mechanical signals that drive osteogenesis.
ATF4 (a member of the bZIP family) is essential in the osteoblast lineage; PTH increases its expression/activity, and part of the PTH-dependent anabolic response requires ATF4, in parallel with the CREB module. Mice with osteoblast-specific deletion of CREB show reduced bone mass, indicating that CREB is required for physiological anabolism.
The role of CREB in osteocytes
In osteocytes PTH, by inactivating protein kinases SIKs, releases CRTC coactivators that migrate to the nucleus and potentiate CREB. This arm stimulates RANKL expression (promoting formation-resorption coupling), while in parallel, PTH, via HDAC4/5→MEF2, represses the SOST (sclerostin) gene, removing a brake on WNT/β-catenin: this combination explains the net anabolic effect of intermittent exposure to PTH/analogues. Small-molecule SIK inhibitors mimic parts of this structure and increase bone mass in mouse models.
Osteoclasts: the modulating role of CREB
The master regulator of osteoclasts is RANKL-induced NFATc1, but CREB participates as a downstream modulator: Ca→CaMKIV/CREB or p38→CREB signals facilitate the induction/nuclear localization of NFATc1 and osteoclast survival. Conversely, certain signals (e.g., dopamine via the D2R receptor, which couples to cAMP/PKA/CREB) reduce osteoclast differentiation. Furthermore, in osteoclasts, p38α uses CREB to induce PDGF-AA and BMP2, mediating coupling with osteoblasts.
CREB in cartilage cells
In the growth plate, PTHrP activates CREB in pre-hypertrophic chondrocytes, supporting proliferation and delaying hypertrophy; CREB cooperates with factors such as AP-1 and intersects with SOX9 programs. Mutations/alterations of these axes disrupt endochondral ossification.
CREB-related bone diseases and treatment opportunities
McCune-Albright fibous dysplasia (GNAS). Activating mutations in GNAS hyperactivate cAMP/PKA→CREB in mesenchymal/osteoblastic cells and impair osteogenesis. A CREB–Smad6–Runx2 axis has been proposed in the “defective osteodifferentiation” of bone marrow stem cells with mutations in the GNAS (G protein alpha subunit) gene.
p53-Deficient Osteosarcoma. Mouse/human models show growth dependence on the PTHrP→cAMP→CREB1 signaling; inhibition of this pathway induces selective arrest and/or apoptosis in p53-deficient osteosarcoma cells, suggesting a therapeutic vulnerability to be exploited.
Common Osteoporosis. Teriparatide and abaloparatide are anabolic PTH receptor agonists. Their anabolic efficacy depends on the early PTH1R→cAMP/PKA→CREB events in the osteoblast/osteocyte lineage. However, other molecules, such as protein kinase inhibitors SIK, intervene in the downstream signaling of the receptors themselves. In preclinical models, experimental compounds such as YKL-05-099, MRT-199665, YKL-06-061, and YKL-06-062 reactivate CRTC/CREB in osteocytes, reduce Sost (via MEF2/HDAC), and increase bone formation.
Finally, pathways that impact CREB (e.g., D2R/dopamine) can attenuate osteoclastogenesis; these are experimental leads for new anti-resorptive or “smart remodeling” therapies. The idea arose from past epidemiological studies suggesting that chronic depression causes the onset of osteoporosis, presumably because dopamine deficiency does not maintain an “inhibitory tone” on osteoclasts, which, over time, would take over from osteoblasts.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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