Master Regulators of Muscle Atrophy: Role of Costamere Components

Abstract

The loss of muscle mass and force characterizes muscle atrophy in several different conditions, which share the expression of atrogenes and the activation of their transcriptional regulators. However, attempts to antagonize muscle atrophy development in different experimental contexts by targeting contributors to the atrogene pathway showed partial effects in most cases. Other master regulators might independently contribute to muscle atrophy, as suggested by our recent evidence about the co-requirement of the muscle-specific chaperone protein melusin to inhibit unloading muscle atrophy development. Furthermore, melusin and other muscle mass regulators, such as nNOS, belong to costameres, the macromolecular complexes that connect sarcolemma to myofibrils and to the extracellular matrix, in correspondence with specific sarcomeric sites. Costameres sense a mechanical load and transduce it both as lateral force and biochemical signals. Recent evidence further broadens this classic view, by revealing the crucial participation of costameres in a sarcolemmal "signaling hub" integrating mechanical and humoral stimuli, where mechanical signals are coupled with insulin and/or insulin-like growth factor stimulation to regulate muscle mass. Therefore, this review aims to enucleate available evidence concerning the early involvement of costamere components and additional putative master regulators in the development of major types of muscle atrophy.

Keywords: aging; atrogene; cachexia; costamere; dystrophin; melusin; muscle atrophy; muscle disuse; nNOS; sarcopenia.

Figure 1

The neuronal NOSμ isoform interacts with the Grp94/gp96 chaperone and is delivered at the subsarcolemma by docking at the DCG. Unloading-induced mitochondrial ROS production causes nNOSμ untethering from DGC and translocation in the sarcoplasm, where the enzyme through either “coupled” or “uncoupled” NADPH oxidation (inset) leads to NO/O₂⁻ production, respectively, and FoxO3 activation. NO = nitric oxide; nNOS = neuronal nitric oxide synthase; SR-ER = sarco-endoplasmic reticulum; IGF1 = insulin-like growth factor 1.

Figure 2

The sarcolemmal costamere components and their interactors form a supramolecular platform specialized in mechanostransduction and signal integration (only a part of the components is shown in the figure). ECM = extracellular matrix; ILK = integrin-linked kinase; MLP = muscle LIM protein; FAK = focal adhesion kinase; nNOS = neuronal nitric oxide synthase; PI3K = phosphoinositide 3-kinase IRS-1 = insulin receptor substrate-1; IGF1R =insulin-like growth factor 1 receptor; SR = sarcoplasmic reticulum.

Figure 3

Signaling pathways activated after a 6–12 h bout of muscle unloading in costameres. Continuous lines indicate stimulatory effects, while discontinuous lines indicate inhibitory effects. Cbl-b = Casitas B-lineage lymphoma-b ubiquitin ligase; Ub = ubiquitin; nNOS = neuronal nitric oxide synthase; FOXO3 = forkhead box O3; MuRF1 = muscle RING-finger protein-1; MAFbx = muscle atrophy F-box; HDAC1 = histone deacetylase 1; Ac = acetylation; IRS-1 = insulin receptor substrate-1; 70S6K = Ribosomal protein S6 kinase p70; P = phosphorylation; AMPK = AMP-activated protein kinase.