The inhibitory role of sympathetic nervous system in the Ca2+-dependent proteolysis of skeletal muscle

Abstract

Mammalian cells contain several proteolytic systems to carry out the degradative processes and complex regulatory mechanisms to prevent excessive protein breakdown. Among these systems, the Ca 2+ -activated proteolytic system involves the cysteine proteases denoted calpains, and their inhibitor, calpastatin. Despite the rapid progress in molecular research on calpains and calpastatin, the physiological role and regulatory mechanisms of these proteins remain obscure. Interest in the adrenergic effect on Ca 2+ -dependent proteolysis has been stimulated by the finding that the administration of β 2 -agonists induces muscle hypertrophy and prevents the loss of muscle mass in a variety of pathologic conditions in which calpains are activated. This review summarizes evidence indicating that the sympathetic nervous system produces anabolic, protein-sparing effects on skeletal muscle protein metabolism. Studies are reviewed, which indicate that epinephrine secreted by the adrenal medulla and norepinephrine released from adrenergic terminals have inhibitory effects on Ca 2+ -dependent protein degradation, mainly in oxidative muscles, by increasing calpastatin levels. Evidence is also presented that this antiproteolytic effect, which occurs under both basal conditions and in stress situations, seems to be mediated by β 2 -and β 3 -adrenoceptors and cAMP-dependent pathways. The understanding of the precise mechanisms by which catecholamines promote muscle anabolic effects may have therapeutic value for the treatment of muscle-wasting conditions and may enhance muscle growth in farm species for economic and nutritional purposes.

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

“…Calpains are calcium-activated proteases, which are inhibited by the protein calpastatin (reviewed in Ref. 168). ␤-AR agonists reduce calpain activity in skeletal muscle tissue in animal models (9,63,169).…”

β2 Adrenoceptor Signaling-induced Muscle Hypertrophy from Blood Flow Restriction: Is There Evidence?

“…One possible PKA dependent mechanism includes an inhibition of calcium dependent proteolysis (e. g., calpains) through an increase in PKA, which could directly or indirectly increase calpastatin [ 20 ] . Calpains are concentrated in the z-lines of skeletal muscle and are involved in protein degradation by disassembling the outer layer of proteins from the myofi bril and releasing them as myofi laments [ 21 ] .…”

“…PKA can directly increase calpastatin through phosphorylation from the PKA catalytic subunits and PKA can indirectly increase calpastatin by increasing the levels of calpastatin mRNA. This increase occurs through an enhancement in gene transcription following the phosphorylation of the cAMP responsive element binding protein (CREB) and the activation of the cAMP responsive element (CRE) [ 20 ] . In addition, gene transcription can be increased through direct phosphorylation of CREB [ 23 ] or indirectly by increasing the expression of the saltinducible kinase 1 (SIK1).…”

Desnutrição perinatal e o controle hipotalâmico do comportamento alimentar e do metabolismo do músculo esquelético

“…No músculo esquelético, as catecolaminas estimulam a oxidação de glicose e ácidos graxos e tem um efeito importante no metabolismo proteico 65 . As análises histoquímicas sugerem que esse efeito seja músculo--específico, sendo mais evidenciado em músculo com predominância de contração rápida e perfil metabólico glicolítico 66 . Outros estudos demonstraram que alterações no SNA e na atividade de enzimas envolvidas no metabolismo lipídico têm sido associadas a doenças como diabetes Mellitus tipo II e obesidade, através de influência sobre o gasto energético 67,68 .…”