Abstract
High expression levels of human double minute-2 (Hdm2) are often associated with increased risk of cancer. Hdm2 is well established as an oncoprotein exerting various tumorigenic effects. Conversely, the physiological functions of Hdm2 in nontumor cells and healthy tissues remain largely unknown. We previously demonstrated that exercise training stimulates expression of murine double minute-2 (Mdm2), the murine analog of Hdm2, in rodent skeletal muscle and Mdm2 was required for exercise-induced muscle angiogenesis. Here we showed that exercise training stimulated the expression of Hdm2 protein in human skeletal muscle from +38% to +81%. This robust physiological response was observed in 60–70% of the subjects tested, in both young and senior populations. Similarly, exercise training stimulated the expression of platelet endothelial cell adhesion molecule-1, an indicator of the level of muscle capillarization. Interestingly, a concomitant decrease in the tumor suppressor forkhead box O-1 (FoxO1) transcription factor levels did not occur with training although Mdm2/Hdm2 is known to inhibit FoxO1 expression in diseased skeletal muscle. This could suggest that Hdm2 has different targets when stimulated in a physiological context and that exercise training could be considered therapeutically in the context of cancer in combination with anti-Hdm2 drug therapies in order to preserve Hdm2 physiological functions in healthy tissues.
Highlights
Expression or function of the tumor suppressor p53 protein is statistically altered in about 50–60% of human cancers (Soussi and Wiman 2007)
The level of muscle vascularization is considered to be an important determinant of exercise capacity (Wagner 2010) and we have previously shown that the level of expression of the platelet endothelial cell adhesion molecule-1 (PECAM-1) protein reflects the level of rodent skeletal muscle vascularization (Roudier et al 2009, 2012)
This is a robust physiological response that occurs in 60–70% of the population independently of age and gender. It illustrates that our previous finding of a stimulatory effect of exercise training on murine double minute-2 (Mdm2) levels in rodent muscle translate to humans
Summary
Expression or function of the tumor suppressor p53 protein is statistically altered in about 50–60% of human cancers (Soussi and Wiman 2007). Mdm involvement in promoting tumor angiogenesis and inflammation has recently emerged through its implication in vascular endothelial growth factor-A (VEGF-A) proangiogenic and NF-jB proinflammatory signaling (Nieminen et al 2005; Carroll and Ashcroft 2008; Busuttil et al 2010; Thomasova et al 2012) With such broad and complex tumorigenic effects, it is not surprising that a search in the Pubmed database indicates that 90% of Mdm2-related publications refer to a tumor context. Whereas prolonged endurance training stimulated Mdm protein expression and promoted angiogenesis in wild-type muscles, the growth of new capillaries was blunted in Mdm2Puro/D7-9 mice. To our knowledge, this is one of very few characterizations of a physiological role for Mdm in an adult and healthy tissue. We hypothesize that the stimulatory effect of exercise training on Mdm muscle expression observed in rodent models will translate into human double minute-2 (Hdm2) protein, the human analog of the murine Mdm, in human skeletal muscle
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