Intracellular signaling in ER stress‐induced autophagy in skeletal muscle cells

Abstract

Skeletal muscle remodeling in response to muscle disuse and unloading is known to be associated with so-called ER stress, which, in turn, activates autophagy and contributes to muscle atrophy. Different molecules are involved in ER stress-induced autophagy, among which PKCθ has recently been described. In this study, we dissected both in vitro and in vivo ER stress-induced autophagy pathways in muscle. Using C2C12 muscle cells in culture, we demonstrated that PKC activation induced autophagy in the absence of ER stress. We further demonstrated that PKCθ was strongly activated in cultured myoblasts and myotubes during ER stress induced by different stimuli, such as TG or TN treatment, and that it localized into Lc3-positive autophagic dots upon TG treatment. Neither Akt dephosphorylation nor Foxo or GSK3β activation was observed in these conditions. Moreover, PKCθ inhibition in myoblasts and myotubes prevented ER stress-induced Lc3 activation and autophagic dot formation, but not ER stress. In vivo, lack of PKCθ prevented both food deprivation- and immobilization-induced autophagy and muscle atrophy, irrespective of Akt pathway inhibition. Taken together, these results demonstrate that PKCθ functions as an ER stress sensor in skeletal muscle, required for ER-stress-dependent autophagy activation, and can be proposed as a novel molecular target to maintain muscle homeostasis in response to external stimuli, such as disuse and unloading, still allowing intracellular clearance.

Overexpression of Smooth Muscle Myosin Heavy Chain Leads to Activation of the Unfolded Protein Response and Autophagic Turnover of Thick Filament-associated Proteins in Vascular Smooth Muscle Cells

“…Activation of JNK downstream of IRE has been shown to induce autophagy by phosphorylating Beclin1 (47). Last, calcium release from the ER during ER stress leads to autophagy through both an AMPK-and mTOR-dependent mechanism and a PKC-dependent mechanism (48,49). SM1 cells have both increased cytosolic calcium levels and AMPK activity, but mTOR activation is also increased compared with wild type cells.…”

Exercise-Induced Skeletal Muscle Remodeling and Metabolic Adaptation: Redox Signaling and Role of Autophagy

“…While excessive autophagy is detrimental to skeletal muscle and contributes to muscle wasting, basal autophagy is required for the maintenance of skeletal muscle homeostasis and integrity (112,161). The autophagylysosome system is activated in several atrophy conditions such as fasting, caloric restriction, cancer cachexia, aging, disuse, and denervation (114,161).…”

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

“…Autophagy constitutes a quality control mechanism, ensuring cell homeostasis and functions. However, its hyperactivation leads to cellular dysfunctions and exacerbates muscle loss in atrophying conditions [113]. In skeletal muscle, myofibrillar proteins targeted by ubiquitin can have a double fate: 1) recognized and removed by the proteasome 26S or 2) docked to the autophagosome.…”