Autophagy-regulating TP53INP2 mediates muscle wasting and is repressed in diabetes

Abstract

A precise balance between protein degradation and synthesis is essential to preserve skeletal muscle mass. Here, we found that TP53INP2, a homolog of the Drosophila melanogaster DOR protein that regulates autophagy in cellular models, has a direct impact on skeletal muscle mass in vivo. Using different transgenic mouse models, we demonstrated that muscle-specific overexpression of Tp53inp2 reduced muscle mass, while deletion of Tp53inp2 resulted in muscle hypertrophy. TP53INP2 activated basal autophagy in skeletal muscle and sustained p62-independent autophagic degradation of ubiquitinated proteins. Animals with muscle-specific overexpression of Tp53inp2 exhibited enhanced muscle wasting in streptozotocin-induced diabetes that was dependent on autophagy; however, TP53INP2 ablation mitigated experimental diabetes-associated muscle loss. The overexpression or absence of TP53INP2 did not affect muscle wasting in response to denervation, a condition in which autophagy is blocked, further indicating that TP53INP2 alters muscle mass by activating autophagy. Moreover, TP53INP2 expression was markedly repressed in muscle from patients with type 2 diabetes and in murine models of diabetes. Our results indicate that TP53INP2 negatively regulates skeletal muscle mass through activation of autophagy. Furthermore, we propose that TP53INP2 repression is part of an adaptive mechanism aimed at preserving muscle mass under conditions in which insulin action is deficient.

Markers of autophagy are adapted to hyperglycaemia in skeletal muscle in type 2 diabetes

“…Although we could not prove a significant insulin-mediated increase in TP53INP2, the muscle transcript levels of TP53INP2 tended to increase in response to insulin in diabetic patients studied at euglycaemia. In contrast to a recent report of decreased muscle expression of TP53INP2 in obesity and type 2 diabetes [44], we could not demonstrate any differences in TP53INP2 levels among lean, obese and diabetic individuals. This is consistent with the similar basal levels of all autophagic markers including p62.…”

“…This is consistent with the similar basal levels of all autophagic markers including p62. In the study of Sala et al [44], the average age in the obese and diabetic groups was much higher than in the lean group, suggesting that this was responsible for reduced TP53INP2 [44]. Overall, our results do not support the hypothesis that TP53INP2 displaces p62 as a cargo receptor as proposed recently [44].…”

“…If the inhibitory action of insulin on autophagy is independent of p62 content in skeletal muscle, as suggested by our data and a recent report [42], then glucose-lowering may increase autophagolysosomal degradation of another cargo receptor causing p62 to accumulate by displacement with no net effect on LCB3 lipidation. Such a p62-independent mechanism involving tumour protein p53 inducible nuclear protein 2 (TP53INP2) was proposed recently [44]. In fact, we observed increased p62 content in patients with type 2 diabetes in response to insulin when studied at euglycaemia.…”

“…In the study of Sala et al [44], the average age in the obese and diabetic groups was much higher than in the lean group, suggesting that this was responsible for reduced TP53INP2 [44]. Overall, our results do not support the hypothesis that TP53INP2 displaces p62 as a cargo receptor as proposed recently [44]. On the other hand, we are unable to provide measurements of TP53INP2 protein levels or studies of co-localisation of p62 and LC3, and of TP53INP2 and LC3, which would be necessary to clearly support or disapprove the hypothesis.…”

Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis

“…One study implicates acetylation of cytoplasmic FoxO1 in the control of autophagy (38). Additionally, the autophagy inducer TP53INP2 is regulated in diabetes, but whether its expression is regulated by FoxOs is unknown (39). Future work should focus on the effect of posttranslational modifications of FoxOs as well as protein-protein interactions with FoxOs during muscle wasting in hopes of better understanding the control of protein turnover by insulin, IGF-1, and FoxOs.…”