Muscle NAD+ depletion and Serpina3n as molecular determinants of murine cancer cachexia-the effects of blocking myostatin and activins.

OBJECTIVE: Cancer cachexia and muscle loss are associated with increased morbidity and mortality. In preclinical animal models, blocking activin receptor (ACVR) ligands has improved survival and prevented muscle wasting in cancer cachexia without an effect on tumour growth. However, the underlying mechanisms are poorly understood. This study aimed to identify cancer cachexia and soluble ACVR (sACVR) administration-evoked changes in muscle proteome. METHODS: Healthy and C26 tumour-bearing (TB) mice were treated with recombinant sACVR. The sACVR or PBS control were administered either prior to the tumour formation or by continued administration before and after tumour formation. Muscles were analysed by quantitative proteomics with further examination of mitochondria and nicotinamide adenine dinucleotide (NAD+) metabolism. To complement the first prophylactic experiment, sACVR (or PBS) was injected as a treatment after tumour cell inoculation. RESULTS: Muscle proteomics in TB cachectic mice revealed downregulated signatures for mitochondrial oxidative phosphorylation (OXPHOS) and increased acute phase response (APR). These were accompanied by muscle NAD+ deficiency, alterations in NAD+ biosynthesis including downregulation of nicotinamide riboside kinase 2 (Nrk2), and decreased muscle protein synthesis. The disturbances in NAD+ metabolism and protein synthesis were rescued by treatment with sACVR. Across the whole proteome and APR, in particular, Serpina3n represented the most upregulated protein and the strongest predictor of cachexia. However, the increase in Serpina3n expression was associated with increased inflammation rather than decreased muscle mass and/or protein synthesis. CONCLUSIONS: We present evidence implicating disturbed muscle mitochondrial OXPHOS proteome and NAD+ homeostasis in experimental cancer cachexia. Treatment of TB mice with a blocker of activin receptor ligands restores depleted muscle NAD+ and Nrk2, as well as decreased muscle protein synthesis. These results indicate putative new treatment therapies for cachexia and that although acute phase protein Serpina3n may serve as a predictor of cachexia, it more likely reflects a condition of elevated inflammation.

Autophagy is induced by resistance exercise in young men, but unfolded protein response is induced regardless of age.

AIM: Autophagy and unfolded protein response (UPR) appear to be important for skeletal muscle homoeostasis and may be altered by exercise. Our aim was to investigate the effects of resistance exercise and training on indicators of UPR and autophagy in healthy untrained young men (n = 12, 27 ± 4 years) and older men (n = 8, 61 ± 6 years) as well as in resistance-trained individuals (n = 15, 25 ± 5 years). METHODS: Indicators of autophagy and UPR were investigated from the muscle biopsies after a single resistance exercise bout and after 21 weeks of resistance training. RESULTS: Lipidated LC3II as an indicator of autophagosome content increased at 48 hours post-resistance exercise (P < .05) and after a resistance training period (P < .01) in untrained young men but not in older men. Several UPRER markers, typically induced by protein misfolding in endoplasmic reticulum, were increased at 48 hours post-resistance exercise in untrained young and older men (P < .05) but were unaltered after the 21-week resistance training period regardless of age. UPR was unchanged within the first few hours after the resistance exercise bout regardless of the training status. Changes in autophagy and UPRER indicators did not correlate with a resistance training-induced increase in muscle strength and size. CONCLUSION: Autophagosome content is increased by resistance training in young previously untrained men, but this response may be blunted by ageing. However, unfolded protein response is induced by an unaccustomed resistance exercise bout in a delayed manner regardless of age.