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  • br TP INP mediated autophagy exacerbates cancer

    2022-07-06


    TP53INP2-mediated autophagy exacerbates cancer-induced muscle wasting
    Provided that cancer-induced muscle wasting could not be prevented by tissue-specific autophagy 
    inhibition and that the formoterol-mediated muscle-sparing effect was not achieved by reduced autoph-agy flux, the next question was whether increasing the autophagy flux would impact on muscle wasting in TB mice. Along this line, Beclin-1 overexpression was excluded since the Meropenem was already strongly increased in the muscle of TB mice. The choice was to modulate TP53INP2/DOR, a positive regulator of autophagy that, however, was previous-ly reported to be down-regulated in muscle-wasting conditions [17]. Muscle TP53INP2 transcript levels were reduced in both C26 and LLC hosts (Fig. 3a) as well as in cachectic cancer patients (Fig. 3b). In particular, TP53INP2 levels were unchanged in non-cachectic patients, suggesting the presence of an adaptive response to cope with an excessive stress-induced autophagy.
    A gain of function experiment performed using transgenic mice overexpressing TP53INP2 in skeletal muscle (Tg mice, hereafter) showed that body weight loss was enhanced in Tg TB mice (Fig. 3c, d), despite that food intake and tumor
    Fig. 2. Formoterol counteracts muscle wasting while maintaining autophagy flux. (a) Body weight changes at the end of the experiment, voluntary grasping strength and tissue masses (GSN, gastrocnemius; TA, tibialis anterior; WAT, gonadal white adipose tissue) in controls (C), C26-bearing male mice (C26) and C26 receiving formoterol (C26 For), n = 6 for all groups. (b) Beclin-1 and LC3B Western blotting analyses in GSN homogenates of the above-mentioned animals. (c) LC3B Western blotting analyses in GSN homogenates of mice receiving colchicine (Col) or vehicle for 2 days before sacrifice. Different letters indicate statistically different results. Statistical significance is set at p b 0.05.
    2678 Autophagy and mitochondria in cancer cachexia
    Fig. 3. TP53INP2 is repressed in atrophic muscles, and muscle overexpression exacerbates body weight loss.
    (d) Body weight changes at the end of the experiment in the above-mentioned animal groups. Different letters indicate statistically different results. Statistical significance is set at p b 0.05.
    burden remained comparable to wild-type (WT) tumor hosts (Fig. S2).
    The exacerbation of body wasting is likely due to excessive muscle protein catabolism. MRI analysis of body composition and the evaluation of tissue weight at necropsy showed a marked loss of lean and muscle mass, respectively, in wild-type (WT) TB mice, that worsened in Tg tumor hosts (Fig. 4a, b). As for the fat mass, a biphasic trend was observed. In the early stages, Tg TB mice showed an accumulation of fat that was progressively lost reaching the same WT levels, confirmed at the end point by the WAT mass (Fig. 4c, d).
    TP53INP2 overexpression resulted in a trend toward increased cancer-induced muscle loss also in female mice, at both early and late stages of cachexia (Fig. S3).
    To understand the molecular alterations associat-ed with muscle wasting in WT and Tg TB mice, the expression of relevant genes was assayed (Fig. 5). 
    Several atrogenes were induced in WT TB mice, atrogin-1 and MuRF1 being further increased in TP53INP2 TB mice, suggesting that both the proteasomal and the autophagic degradation con-tribute to the increased muscle protein catabolism. Autophagy was reported to be strongly induced in cachectic muscles [5] and in keeping with those data an enhanced expression of autophagy genes (LC3, GABARAPL1, p62, LAMP2A, BNIP3) was detected in the muscle of WT C26 hosts. In TP53INP2 TB mice, transcript levels for all the Meropenem assayed genes were comparable to WT C26 hosts, despite the role played by TP53INP2 in autophagic degradation, implying that TP53INP2-induced catabolism is not mediated by transcriptional regulation. Beyond bulk or selective autophagy, mitochondrial dynamics modulates muscle wasting as well [12,18]. In the present study, BNIP3 mRNA was similarly induced in WT and Tg TB mice, whereas both mitochondrial