Neurobiology of Aging 32 (2011) 2190–2197 Telomere shortening is associated to TRF1 and PARP1 overexpression in Duchenne muscular dystrophy M’Hammed Aguennouz a,1 , Gian Luca Vita a,1 , Sonia Messina a , Annamaria Cama a , Natalia Lanzano a , Annamaria Ciranni a , Carmelo Rodolico a , Rosa Maria Di Giorgio b , Giuseppe Vita a,∗ a Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, AOU Policlinico, Messina 98125, Italy b Department of Biochemical, Physiological and Nutritional Sciences, University of Messina, AOU Policlinico, Messina 98125, Italy Received 23 July 2009; received in revised form 30 October 2009; accepted 14 January 2010 Available online 5 February 2010 Abstract Telomere shortening is thought to contribute to premature senescence of satellite cells in Duchenne muscular dystrophy (DMD) muscle. Telomeric repeat binding factor-1 (TRF1) and poly (ADP-ribose) polymerase-1 (PARP1) are proteins known to modulate telomerase reverse transcriptase (TERT) activity, which controls telomere elongation. Here we show that an age-dependent telomere shortening occurs in DMD muscles and is associated to overexpression of mRNA and protein levels of TRF1 and PARP1. TERT expression and activity are detectable in normal control muscles and they slightly increase in DMD. This is the first demonstration of TRF1 and PARP1 overexpression in DMD muscles. They can be directly involved in replicative senescence of satellite cells and/or in the pathogenetic cascade through a cross-talk with oxidative stress and inflammatory response. Modulation of these events by TRF1 or PARP1 inhibition might represent a novel strategy for treatment of DMD and other muscular dystrophies. © 2010 Elsevier Inc. All rights reserved. Keywords: Telomere shortening; TRF1; PARP1; Duchenne muscular dystrophy; Replicative senescence 1. Introduction Telomeres are short, repeated sequences of TTAGGG located at the end of chromosomes which are involved in several essential biological functions (Cong et al., 2002). Telomeres contribute to the functional organization of chro- mosomes, participate in the regulation of gene expression, and serve as a molecular clock that controls the replica- tive capacity of the cells. In somatic cells, telomeres shorten with successive cell divisions, and it results in progressive genomic instability and altered gene expression, contributing to replicative senescence, apoptosis or neoplastic transfor- mation (Blasco, 2005). Despite this apparently inevitable ∗ Corresponding author. Unit of Neurology and Neuromuscular Diseases, AOU Policlinico, Via Consolare Valeria 1, 98125 Messina, Italy. Tel.: +39 090 2212793; fax: +39 090 2212789. E-mail address: vitag@unime.it (G. Vita). 1 Both authors equally contributed to this study. phenomenon, telomere length does not change considerably from generation to generation in mammals, indicating the existence of some mechanism to maintain telomeres. That mechanism turns out to be the expression of telomerase, a ribonucleoprotein enzyme complex composed of an RNA subunit and a catalytic protein subunit called telomerase reverse transcriptase (TERT), which is the rate-limiting factor for the enzyme activity (Shay and Wright, 2004). Telomerase synthesizes telomeric repeats onto chromosome ends by use of an endogenous ribonucleic acid as a template and provides the molecular basis for unlimited proliferative potential in the germline and also in somatic cells (Flores et al., 2006). The existence of a telomerase-independent mechanism, at least in cancer cells, further complicates this issue (Reddel, 2003). The shortening of telomeres may be due not only to loss of tandem repeats during replication, but also to direct oxida- tive damage to telomeres (von Zglinicki, 2002). Based on the evidence that oxidative stress may be a key mediator of the aging process in general, this suggests that telomere length 0197-4580/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2010.01.008