Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats

Abstract

The tumor suppressor p53 is thought to play a key role in the maintenance of cell size and homeostasis, but relatively little is known about its role in skeletal muscle. Based on its ability to suppress cell growth, we hypothesized that inhibiting the function of wild-type p53 through the overexpression of a dominant-negative p53 mutant (DDp53) could result in muscle fiber hypertrophy. To test this hypothesis, we electroporated adult rat tibialis anterior muscles with DDp53 and collected the tissue three weeks later. We confirmed successful overexpression of DDp53 on a histological and biochemical level and found pronounced changes to muscle architecture, metabolism, and molecular signaling. Muscle mass, fiber cross-sectional area, and fiber diameter significantly decreased with DDp53 overexpression. We found histopathological changes in DDp53 transfected muscle which were accompanied by increased levels of proteins that are associated with membrane damage and repair. In addition, DDp53 decreased oxidative phosphorylation complex I and V protein levels, and despite its negative effects on muscle mass and fiber size, caused an increase in muscle protein synthesis as assessed via the SUnSET technique. Interestingly, the increase in muscle protein synthesis was concomitant with a decrease in phospho-S6K1 (Thr389). Furthermore, the muscle wasting in the DDp53 electroporated leg was accompanied by a decrease in global protein ubiquitination and an increase in proteasome activity. In conclusion, overexpression of a dominant-negative p53 mutant in skeletal muscle results in decreased muscle mass, myofiber size, histological muscle damage, a metabolic phenotype, and perturbed homeostasis between muscle protein synthesis and degradation.

Age-Associated Differences in Recovery from Exercise-Induced Muscle Damage

“…This suggests that measuring MPS does not necessarily reflect net protein accrual, but rather the remodeling state of muscle. In agreement with this, it has been shown in rodents that MPS and associated anabolic signals can be increased in scenarios where overall muscle mass is lost rather than gained [74][75][76][77]. Indeed, pre-clinical and clinical studies suggest that the amount of muscle damage in response to RE might be more pronounced in older compared to younger individuals [56,78].…”

Eliminating elevated p53 signaling fails to rescue skeletal muscle defects or extend survival in lamin A/C-deficient mice

“…2 ). How chronic stabilization of p53 negatively influences myofiber function is not clear, as the role of p53 in skeletal muscle has largely been investigated with loss-of-function studies [ 41 , 43 , 44 , 60 ]. Recent data suggests that in addition to its classically described role as a transcription factor, cytoplasmic p53 also plays important biological functions, including suppressing autophagy [ 61 ], mitochondrial permeability and production of reactive oxygen species [ 62 , 63 ], and modulation of Ca 2+ homeostasis between mitochondria and endoplasmic reticulum [ 64 ].…”

Role of p53 in Cisplatin-Induced Myotube Atrophy

“…Studies have also shown that p53 overexpression leads to the emergence of senescent traits and muscle atrophy [33,37], and muscle-specific p53-knockout (KO) mice were partially resistant to immobilization-induced skeletal muscle atrophy [33]. Conversely, muscle atrophy was induced in a p53 loss-offunction model created through the overexpression of dominant-negative p53 protein [38]. In an animal model of immobilization, the degree of muscle atrophy was found to be similar between muscle-specific p53-KO mice and wild-type mice [36], and aging-related muscle atrophy was not suppressed in the same KO mice described above [39].…”