Sustained Activation of mTORC1 in Skeletal Muscle Inhibits Constitutive and Starvation-Induced Autophagy and Causes a Severe, Late-Onset Myopathy

Abstract

Autophagy is a catabolic process that ensures homeostatic cell clearance and is deregulated in a growing number of myopathological conditions. Although FoxO3 was shown to promote the expression of autophagy-related genes in skeletal muscle, the mechanisms triggering autophagy are unclear. We show that TSC1-deficient mice (TSCmKO), characterized by sustained activation of mTORC1, develop a late-onset myopathy related to impaired autophagy. In young TSCmKO mice, constitutive and starvation-induced autophagy is blocked at the induction steps via mTORC1-mediated inhibition of Ulk1, despite FoxO3 activation. Rapamycin is sufficient to restore autophagy in TSCmKO mice and improves the muscle phenotype of old mutant mice. Inversely, abrogation of mTORC1 signaling by depletion of raptor induces autophagy regardless of FoxO inhibition. Thus, mTORC1 is the dominant regulator of autophagy induction in skeletal muscle and ensures a tight coordination of metabolic pathways. These findings may open interesting avenues for therapeutic strategies directed toward autophagy-related muscle diseases.

Rhabdomyolysis-Associated Mutations in Human LPIN1 Lead to Loss of Phosphatidic Acid Phosphohydrolase Activity

“…Mutations in lipin 1 PAP activity would be predicted to increase the cellular PA concentration, which may be toxic and/or activate inflammatory MAPK signaling cascades (Nadra et al 2008). PA also activates mTORC1 kinase (Sun and Chen 2008;Mitra et al 2013), which has been linked to development of muscle injury and myopathy (Castets et al 2013) Leu635Pro (*P < 0.05, t-test). (c) Coomassie stain and PAP activity of purified recombinant WT lipin 1, p.Leu635Pro, and p.Arg725His.…”

Myelination and mTOR

“…In contrast, under stress conditions such as energy depletion resulting in an increased AMP to ATP ratio, the protein kinase AMPK is activated through phosphorylation by upstream kinases, such as LKB1 (Hardie, Ross, & Hawley, 2012), and phosphorylates TSC2 to enhance its GAP activity (Inoki, Zhu, & Guan, 2003). Thus, since the TSC complex integrates multiple upstream signals to negatively regulate a key step in mTORC1 activation, its disruption causes constitutive mTORC1 activation (Byles et al, 2013; Castets et al, 2013; Kwiatkowski et al, 2002). …”

Looking at the metabolic consequences of the colchicine-based in vivo autophagic flux assay

“…10,11 It has thus been shown that intraperitoneal (IP) injection of leupeptin triggers significant accumulation of LC3-II in liver as early as 30 to 60 min after the treatment, 10 whereas most of the studies focusing on skeletal muscle treated mice for no less than 2 d (i.e., a daily injection from 2 to 10 d). 9,[11][12][13] As a consequence, the prolonged use of these drugs could induce collateral effects that might directly or indirectly affect autophagy. For instance, Ju et al report that both LC3-I and LC3-II levels increase in skeletal muscle of mice treated with colchicine beyond 5 d, suggesting that the long-period treatments induce autophagic flux blockage but also enhance autophagy.…”