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

Abstract

Berdeaux R, Stewart R. cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration. Am J Physiol Endocrinol Metab 303: E1-E17, 2012. First published February 21, 2012 doi:10.1152/ajpendo.00555.2011.-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, agerelated 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 ORIGINALLY DISCOVERED by Sutherland and Rall in liver homogenates in 1958 (218), adenosine 3=,5=-monophosphate (cyclic AMP, or cAMP) has since been intensively studied and is one of the best-characterized signaling molecules. In skeletal muscle, acute cAMP signaling has been implicated in regulation of glycogenolysis (213), contractility (32,83,84,88,138,234), sarcoplasmic calcium dynamics (58,147,184,204), and recovery from sustained contractile activity (44, 162). The net result of acute cAMP action on the order of minutes in skeletal muscle can generally be described as increased contractile force and rapid recovery of ion balance, especially during prolonged contractions. These acute changes are most pertinent to muscle contraction and energy utilization during exercise, when epinephrine is rapidly released into the circulation (92) and cAMP accumulates in muscle (72).Many studies have shown, however, that cAMP-inducing agents or genetic modification of proteins involved in cAMP signaling can also have adaptive effects on skeletal muscle by increasing myofiber size and promoting fiber-type transitions to glycolytic fibers (9,18,42,43,57,63,86,91,101,121,128,154,155,163,190,193,194,215). The prohypertrophic actions of ␤-adrenergic receptor (␤-AR) agonists and corticotropin-releasing factor recept...

Regulation of SIK1 abundance and stability is critical for myogenesis

“…This would allow cells to rapidly return to a resting state after the cAMP signal decays. In vivo, exercise or activation of the "fight-or-flight response" causes catecholamine release from the adrenal medulla, resulting in cAMP accumulation in skeletal muscle and other tissues (5). We hypothesize that in this setting if muscle precursor cells responded with induction of Sik1, the protein would be rapidly degraded.…”

“…M yoblast differentiation is driven by a transcriptional cascade that is subject to precise temporal control during development as well as after acute muscle injury (1). The second messenger cAMP and its primary effector PKA are known to contribute to myoblast proliferation in the developing dermomyotome (2), to promote migration and fusion of muscle precursor cells (3,4), and to exert potent anabolic effects on adult skeletal muscle (5). During differentiation of myoblasts ex vivo, intracellular cAMP peaks transiently before cell-cell fusion (6,7), and PKA signaling is required for expression of differentiation markers in cultured myoblasts (8) and in mouse embryos (2).…”

“…The mechanisms by which a transient peak of cAMP promotes myoblast differentiation are still poorly understood. Because ligands that induce cAMP production promote muscle regeneration (5), it is important to identify promyogenic cAMP signaling effectors.…”

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

“…Signals via cAMP/PKA pathway control the development (Chen et al 2005a, Knight & Kothary 2011) and metabolism (Berdeaux & Stewart 2012) of skeletal muscle, which plays an essential role in the regulation of glucose homeostasis (Stump et al 2006). As mentioned above, liver and skeletal muscle are the major sites for glycogen storage.…”

Role of Masseter Muscle β2-Adrenergic Signaling in Regulation of Muscle Activity, Myosin Heavy Chain Transition, and Hypertrophy

“…As a consequence of its muscle anabolic properties, CB might have therapeutic potential for the treatment of muscle wasting associated with sarcopenia, cancer cachexia, sepsis, denervation, disuse, inactivity, unloading, microgravity, or heart failure, although it is necessary to obviate cardiovascular side-effects (4). The b 2 -adrenergic signaling pathways responsible for CB-induced hypertrophy have been well studied, often with the aim of identifying novel therapeutic targets for the treatment of muscle-wasting disorders, and it appears that b 2 -AR stimulation with CB can increase protein synthesis and inhibit protein degradation through activation of the Akt and/or protein kinase A signaling pathways (4,7). Adult skeletal muscle is composed of muscle fibers that differ in their speed of contraction and predominant type of energy metabolism.…”