Endocrinology and Metabolism

cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration

Rebecca Berdeaux, Randi Stewart

Abstract

Among organ systems, skeletal muscle is perhaps the most structurally specialized. The remarkable subcellular architecture of this tissue allows it to empower movement with instructions from motor neurons. Despite this high degree of specialization, skeletal muscle also has intrinsic signaling mechanisms that allow adaptation to long-term changes in demand and regeneration after acute damage. The second messenger adenosine 3′,5′-monophosphate (cAMP) not only elicits acute changes within myofibers during exercise but also contributes to myofiber size and metabolic phenotype in the long term. Strikingly, sustained activation of cAMP signaling leads to pronounced hypertrophic responses in skeletal myofibers through largely elusive molecular mechanisms. These pathways can promote hypertrophy and combat atrophy in animal models of disorders including muscular dystrophy, age-related atrophy, denervation injury, disuse atrophy, cancer cachexia, and sepsis. cAMP also participates in muscle development and regeneration mediated by muscle precursor cells; thus, downstream signaling pathways may potentially be harnessed to promote muscle regeneration in patients with acute damage or muscular dystrophy. In this review, we summarize studies implicating cAMP signaling in skeletal muscle adaptation. We also highlight ligands that induce cAMP signaling and downstream effectors that are promising pharmacological targets.

  • cyclic AMP
  • skeletal muscle
  • cell signaling
  • muscle regeneration
  • atrophy
  • protein kinase A
  • Glossary

    Akt
    Protein kinase B, PKB
    AKAP
    A-kinase anchoring protein
    AVP
    Arg8-vasopressin
    β-AR
    β-Adrenergic receptor
    cAMP
    Adenosine 3′,5′-monophosphate
    CGRP
    Calcitonin gene-related peptide
    COXIV
    Cytochrome c oxidase, subunit IV
    CREB
    cAMP response element-binding protein
    CRF
    Corticotropin-releasing factor
    CRFR2
    Corticotropin-releasing factor receptor 2
    CXCR4
    CXC chemokine receptor 4
    dy/dy
    Laminin-deficient mouse with muscular dystrophy
    Epac
    Exchange protein activated by cAMP
    ERK1/2
    Extracellular signal-regulated kinases 1 and 2
    Forskolin
    Direct AC agonist
    FoxO
    Forkhead box transcription factors, class O
    Fzd7
    Frizzled 7
    GPCR
    G protein-coupled receptor
    IGF-I
    Insulin-like growth factor I
    IL-6
    Interleukin-6
    LTCC
    L-type calcium channel
    MAFbx
    Muscle atrophy F-box, Atrogin 1
    mdx
    Dystrophin-deficient mouse strain
    MuRF1
    Muscle RING finger 1
    MyHC
    Myosin heavy chain
    nAChR
    Nicotinic acetylcholine receptor
    NMJ
    Neuromuscular junction
    Nor1
    Neuron-derived orphan receptor 1, also Nr4a3
    Nur77
    Nuclear receptor family member 77, also Nr4a1
    PI 3-kinase
    Phosphatidylinositol 3-kinase
    MAP kinase
    Mitogen-activated protein kinase
    PGC1-α
    PPARγ coactivator 1α
    PKA
    cAMP-dependent protein kinase, protein kinase A
    PKC
    Protein kinase C
    RhoGDI
    RhoGTPase guanine nucleotide dissociation inhibitor
    RyR
    Ryanodine receptor
    SR
    Sarcoplasmic reticulum
    SERCA
    Sarco/endoplasmic reticulum Ca2+-ATPase
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