Conditional over-expression of PITX1 causes skeletal muscle dystrophy in mice

Abstract

Summary Paired-like homeodomain transcription factor 1 (PITX1) was specifically up-regulated in patients with facioscapulohumeral muscular dystrophy (FSHD) by comparing the genome-wide mRNA expression profiles of 12 neuromuscular disorders. In addition, it is the only known direct transcriptional target of the double homeobox protein 4 (DUX4) of which aberrant expression has been shown to be the cause of FSHD. To test the hypothesis that up-regulation of PITX1 contributes to the skeletal muscle atrophy seen in patients with FSHD, we generated a tet-repressible muscle-specific Pitx1 transgenic mouse model in which expression of PITX1 in skeletal muscle can be controlled by oral administration of doxycycline. After PITX1 was over-expressed in the skeletal muscle for 5 weeks, the mice exhibited significant loss of body weight and muscle mass, decreased muscle strength, and reduction of muscle fiber diameters. Among the muscles examined, the tibialis anterior, gastrocnemius, quadricep, bicep, tricep and deltoid showed significant reduction of muscle mass, while the soleus, masseter and diaphragm muscles were not affected. The most prominent pathological change was the development of atrophic muscle fibers with mild necrosis and inflammatory infiltration. The affected myofibers stained heavily with NADH-TR with the strongest staining in angular-shaped atrophic fibers. Some of the atrophic fibers were also positive for embryonic myosin heavy chain using immunohistochemistry. Immunoblotting showed that the p53 was up-regulated in the muscles over-expressing PITX1. The results suggest that the up-regulation of PITX1 followed by activation of p53-dependent pathways may play a major role in the muscle atrophy developed in the mouse model.

Apoptotic Mediators are Upregulated in the Skeletal Muscle of Chronic/Progressive Mouse Model of Parkinson's Disease

“…4B). Our observation of the angular profiles of the atrophic PD muscle fibers is in line with the previous studies reporting the morphological characteristics for skeletal muscle atrophy (Sakkas et al, 2003;Doppler et al, 2008;Pandey et al, 2012;Hara et al, 2013;Werneck et al, 2013). Additionally, muscle atrophy indicated by significant decline in muscle fiber cross-sectional area (Figs.…”

Nodal Pathway Genes Are Down-regulated in Facial Asymmetry

“…Pitx2 is required for initiation and progression of myogenic lineage of masticatory muscles, 42 and overexpression of Pitx1 may cause skeletal muscle fiber atrophy. 40 Masseter muscle samples from the side opposite of the chin deviation had increased expression of Pitx1 compared to muscle from symmetric subjects (Table 1). Fast-contracting type II fibers of masseter muscle on this facial side have decreased cell number and cell size, which could be an effect from increased Pitx1 expression.…”

“…39 PITX1 , another member of the PITX gene family, produces fiber atrophy when overexpressed in masseter muscle. 40 Collectively, these findings suggest that Nodal Pathway genes are active in adult skeletal muscle and may be key factors in development, growth and maintenance of facial asymmetry. In order to determine if symmetry pathways are active in adult humans we compared gene expression in masseter muscle between dentofacial deformity subjects with and without facial asymmetry.…”

Targeting mRNA for the treatment of facioscapulohumeral muscular dystrophy

“…Studies have found that the PITX1 gene is 10-20 times up-regulated in the muscle fibers of FSHD patients. The role of PITX1 in myopathy was shown in vivo via a tet-repressible muscle-specific PITX1 transgenic mouse model (78,79). The PITX1 transgenic mouse model with overexpression of PITX1 in skeletal muscles demonstrates a similar disease phenotype to the muscular dystrophy seen in FSHD patients.…”