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  • Paclitaxel (Taxol) br autophagy blockade Such a


    autophagy blockade. Such a hypothesis was previ-ously demonstrated in colon cancer Paclitaxel (Taxol) [21], although convincing evidence in the skeletal muscle is lacking. In this regard, previous data reported that either proteasome [4] or calpain [22] inhibition does not improve cancer-induced muscle wasting, in agreement with the idea that targeting a specific proteolytic system likely leads to Paclitaxel (Taxol) compensatory activation of the others, vanishing treatment effec-tiveness. The other way round, simultaneously blocking more than one proteolytic system likely results in potential cumulative side effects, consid-ering the reported accumulation of p62 upon beclin-1 knockdown, although a phase 1 clinical trial using both proteasome and autophagy inhibitors was reported in patients with relapsed/refractory myelo-ma [23].
    While blocking autophagy does not exert beneficial effect on cancer-induced muscle wasting, the resto-ration of normal muscle mass achieved by formoterol is associated with the preservation of the autophagy flux, supporting the idea that direct blockade of protein degradation should not be pursued. Few studies tried to uncover the mechanism underlying formoterol
    Autophagy and mitochondria in cancer cachexia 2681
    Fig. 6. C26 tumor growth impairs muscle mitochondrial function through mitophagy. (a) Ex vivo mitochondrial respiration in permeabilized extensor digitorum longus (EDL) fiber bundles of controls (C) and C26-bearing mice (C26) either WT (n = 5 for C and 9 for C26) or overexpressing TP53INP2 specifically in the skeletal muscle (Tg; n = 7 for C and 9 for C26). (b) Immunofluorescence images of TA muscle sections stained for BNIP3 (red) and SDH (green). Western blotting performed on cytosolic (c) or mitochondrial (d) enriched gastrocnemius (GSN) muscle fractions. Different letters indicate statistically different results. Statistical significance is set at p b 0.05.
    effect on muscle proteolysis in both healthy [24] and wasting (cancer-related) conditions [25,26]. The results of these studies show that formoterol treatment was associated with proteasome inhibition in the skeletal muscle, with beneficial effect on autophagy static markers. The present data, demonstrating that autophagy flux is maintained upon formoterol admin-istration suggest that autophagy is required to maintain muscle mass even in TB animals. Indeed, given the positive effect exerted by formoterol on muscle mass and strength, we speculate that a preserved, although not exaggerated, autophagy flux is crucial in the maintenance of muscle function. Along this line, it is very likely that blocking protein catabolism could improve muscle mass but not necessarily muscle quality. Indeed, p62 accumulation in the muscle of TB mice upon autophagy blockade likely reflects an engulfment of proteins and organ-elles tagged for degradation, which arguably contrib-utes to reduced muscle function. Moreover, colchicine, a highly toxic microtubule disorganizer that impairs autophagy, leads to sudden death of TB animals [5]. This observation suggests that in parallel 
    to the drug toxicicy, autophagy blockade in wasted anorectic individuals potentially results in a dangerous systemic energy deficit.
    Consistently, survival of TB mice is not impaired when autophagy is induced in the skeletal muscle by TP53INP2 overexpression, at least in the experi-mental settings adopted in this study, although muscle protein depletion is exacerbated. Previous data suggested that TP53INP2 repression was part of an adaptive mechanism aimed at preserving muscle mass upon insulin deficiency or insulin resistance [10,17]. Merging this latter information with the present results, showing that TP53INP2 expression is reduced in both TB mice and cancer patients, the existence of a regulatory mechanism that suppresses TP53INP2 when excessive prote-olysis occurs can be proposed. The sensor for such mechanism is far from being identified, and it is still unknown whether the trigger is the catabolic condition or the energy deficiency. The observation that muscle TP53INP2 expression increases when shifting from a diet providing the 18% to another providing the 80% of energy from fat [27] suggests r> 2682 Autophagy and mitochondria in cancer cachexia
    the presence of a control based on nutrient availability, leading to TP53INP2 activation under substrate abundance and suppression upon nutrient shortage. Since TP53INP2 is an important player in basal autophagy [28,29], which is in charge of degrading damaged organelles and aggregated and/or misfolded proteins, its down-regulation in wasted muscles might predict poor muscle quality despite excessive unselective stress-induced deg-radation. Cargo selectivity is an important feature of basal autophagy, a crucial quality control mecha-nism important for the maintenance of cell and tissue homeostasis [30]. From a speculative standpoint, TP53INP2 might be part of a protein/organelle quality control system, activated only in the presence of substrate abundance, shifting the balance toward improved quality in spite of reduced energy availability. Consistently, in fasted TP53INP2 Tg mice, muscle proteolysis is enhanced while high mitochondrial efficiency occurs in normal feeding conditions.