Autophagy Exacerbates Muscle Wasting in Cancer Cachexia and Impairs Mitochondrial Function

Abstract

Cancer cachexia is a multifactorial syndrome characterized by anorexia, weight loss and muscle wasting that impairs patients' quality of life and survival. Aim of this work was to evaluate the impact of either autophagy inhibition (knocking-down beclin-1) or promotion (overexpressing TP53INP2/DOR) on cancer-induced muscle wasting. In C26 tumor-bearing mice, stress-induced autophagy inhibition was unable to rescue the loss of muscle mass and worsened muscle morphology. Treating C26-bearing mice with formoterol, a selective β2-agonist, muscle sparing was paralleled by reduced static autophagy markers although the flux was maintained. Conversely, the stimulation of muscle autophagy exacerbated muscle atrophy in tumor-bearing mice. TP53INP2 further promoted atrogene expression and suppressed mitochondrial dynamics-related genes. Excessive autophagy might impair mitochondrial function through mitophagy. Consistently, tumorinduced mitochondrial dysfunction was detected by reduced ex vivo muscle fiber respiration. Overall, the results evoke a central role for muscle autophagy in cancer-induced muscle wasting. Highlights  Autophagy contribution to cancer-related muscle wasting is still debated.  Blocking muscle stress-induced autophagy is unable to spare muscle mass.  Formoterol counteracts muscle wasting without blocking autophagy flux.  Muscle-specific autophagy induction via TP53INP2 overexpression exacerbates cachexia.

The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?

“…However, autophagy induction in cancer cachexia is peculiar in comparison with other muscle wasting-associated states: instead of being degraded, autophagosomes do accumulate in the tissue, probably reflecting lysosomal engulfment and protease activity exhaustion (95). Consistently with these observations, both inhibition and overstimulation of autophagy are detrimental in tumor-bearing mice (92,95).…”

Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities consistent with exacerbated cachexia

“…We also identified STAT1 as an upstream regulator within mC26 skeletal muscle. Interestingly, STAT1 has recently been implicated as a regulator of autophagy, a degradation process known to be upregulated in cachectic cancer patients and animal models of cachexia (57)(58)(59). Future studies will interrogate these pathways to better understand the mechanisms by which formation of LMs differentially alter skeletal muscle signaling.…”

Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy

“…In both of these models, IGF-1 is reduced [ 73 , 74 ] and IGF-1 administration rescued muscle atrophy [ 39 , 75 , 76 ]. However, in C26 tumor-bearing mice, neither inhibition nor activation of autophagy rescued the muscle function, and both treatments worsened the outcome [ 77 ]. The IGF-1 pathway could still be a promising target to treat muscle atrophy where both autophagy and UPS are activated, and protein synthesis is decreased, as IGF-1 activation could theoretically normalize all of these pathways.…”