Abstract
Mechanisms of muscle atrophy are complex and their understanding might help finding therapeutic solutions for pathologies such as amyotrophic lateral sclerosis (ALS). We meta-analyzed transcriptomic experiments of muscles of ALS patients and mouse models, uncovering a p53 deregulation as common denominator. We then characterized the induction of several p53 family members (p53, p63, p73) and a correlation between the levels of p53 family target genes and the severity of muscle atrophy in ALS patients and mice. In particular, we observed increased p63 protein levels in the fibers of atrophic muscles via denervation-dependent and -independent mechanisms. At a functional level, we demonstrated that TAp63 and p53 transactivate the promoter and increased the expression of Trim63 (MuRF1), an effector of muscle atrophy. Altogether, these results suggest a novel function for p63 as a contributor to muscular atrophic processes via the regulation of multiple genes, including the muscle atrophy gene Trim63.
Highlights
Muscle atrophy is associated with aging, cancer, AIDS and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS)
We developed a comprehensive approach combining biopsies from ALS patients, transgenic animal model of ALS and myoblastic cell lines to analyse the expression and the possible function of P63, a member of the p53 family, in muscle atrophy
Our results demonstrate that there is a complex p53-like response developed by the atrophic muscle during ALS progression
Summary
Muscle atrophy is associated with aging, cancer, AIDS and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) (von Haehling et al, 2010). In the case of a neurodegenerative disease called amyotrophic laterals sclerosis (or ALS), it is the muscle degeneration that leads to the death of patients within a few years. Protein aggregates or other alterations induced by SOD1 mutants have been characterized in muscle cells, while other mutated proteins linked to ALS seem to not directly affect muscles (Pansarasa et al, 2014). DN isoforms lack such a domain and can serve as dominant negatives versus the TA isoforms in some cases, they are capable of transactivating certain genes (De Laurenzi et al, 1998; Casciano et al, 1999; MurrayZmijewski et al, 2006) Through their cellular activities, p53 proteins are involved in a broad variety of physiological functions that include tumor suppression and organ development (Arrowsmith, 1999). We investigated the regulation and the role of the transcription factors of the p53 family in muscular atrophy during ALS based on a meta-analysis we performed with 4 microarray experiments obtained with biopsies of muscles from ALS patients or with muscles from ALS mouse models
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
