Inhibition of extracellular signal-regulated kinase 1/2 signaling has beneficial effects on skeletal muscle in a mouse model of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutation
© Muchir et al.; licensee BioMed Central Ltd. 2013
Received: 3 January 2013
Accepted: 22 April 2013
Published: 1 July 2013
Autosomal Emery-Dreifuss muscular dystrophy is caused by mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. Classically, the disease manifests as scapulo-humeroperoneal muscle wasting and weakness, early joint contractures and dilated cardiomyopathy with conduction block; however, move variable skeletal muscle involvement can be present. Previously, we demonstrated increased activity of extracellular signal-regulated kinase (ERK) 1/2 in hearts of LmnaH222P/H222P mice, a model of autosomal Emery-Dreifuss muscular dystrophy, and that blocking its activation improved cardiac function. We therefore examined the role of ERK1/2 activity in skeletal muscle pathology.
Sections of skeletal muscle from LmnaH222P/H222P mice were stained with hematoxylin and eosin and histological analysis performed using light microscopy. ERK1/2 activity was assessed in mouse tissue and cultured cells by immunoblotting and real-time polymerase chain reaction to measure expression of downstream target genes. LmnaH222P/H222P mice were treated with selumetinib, which blocks mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 that activates ERK1/2, from 16 to 20 weeks of age to assess the effects of treatment on muscle histology, ERK1/2 activity and limb grip strength.
We detected enhanced activation of ERK1/2 in skeletal muscle of LmnaH222P/H222P mice. Treatment with selumetinib ameliorated skeletal muscle histopathology and reduced serum creatine phosphokinase and aspartate aminotransferase activities. Selumetinib treatment also improved muscle function as assessed by in vivo grip strength testing.
Our results show that ERK1/2 plays a role in the development of skeletal muscle pathology in LmnaH222/H222P mice. They further provide the first evidence that a small molecule drug may be beneficial for skeletal muscle in autosomal Emery-Dreifuss muscular dystrophy.
KeywordsMuscular dystrophy Nuclear envelope Lamin Selumetinib Mitogen-activated protein kinase
Emery-Dreifuss muscular dystrophy (EDMD) is classically characterized clinically by a triad of: (1) slowly progressive muscle weakness and wasting in a scapulo-humeroperoneal distribution; (2) early contractures of the elbows, ankles, and posterior neck; and (3) dilated cardiomyopathy with conduction defects [1, 2]. Contractures are usually the first clinical sign of the disease occurring in the first decade of life. During the second decade of life, the slowly progressive muscle weakness and wasting typically begin. At the end of the second decade, most patients develop evidence of cardiomyopathy [3–5].
EDMD can be inherited in a X-linked or autosomal fashion. X-linked EDMD is caused by mutations in EMD encoding emerin . Emerin is an integral protein of the inner nuclear membrane [7, 8]. The majority of autosomal dominant and less frequent recessive cases are caused by mutations in LMNA[9, 10]. LMNA encodes two major somatic cell polypeptides, lamin A and lamin C, which are components of the nuclear lamina, a meshwork of intermediate filaments on the inner aspect of the inner nuclear membrane [11–14]. While the classical EDMD phenotype was first attributed to EMD and LMNA mutations, it is now apparent that the same mutations in these genes can cause dilated cardiomyopathy with more variable skeletal muscle involvement [6, 9, 15–21]. Intriguingly, LMNA mutations (different than those leading to myopathy) can also cause partial lipodystrophy, peripheral neuropathy, or accelerated aging disorders such as Hutchinson-Gilford progeria syndrome .
Despite the relatively recent advances in understanding the genetics of EDMD and related myopathies, the pathogenic mechanisms leading to striated muscle damage are only poorly understood. One useful small animal model to study pathogenesis and evaluate potential therapeutic interventions in autosomal EDMD is the LmnaH222P/H222P mouse . Starting at approximately 16 weeks, male LmnaH222P/H222P develop progressive dystrophic pathology in several skeletal muscle groups. Later, they have progressive accumulation of connective tissue in skeletal muscle. LmnaH222P/H222P mice also develop dilated cardiomyopathy with conduction system abnormalities and significant cardiac fibrosis.
We have previously shown that LmnaH222P/H222P mice have increased activity of the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) 1/2 in cardiac muscle . This increased ERK1/2 activity occurs prior to the onset of overt tissue pathology, suggesting that it plays a primary pathogenic role. Treatment of LmnaH222P/H222P mice with drugs that inhibit mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) 1/2, the kinase that activates ERK1/2, leads to improved left ventricular ejection fraction [25, 26], decreased cardiac fibrosis [26, 27] and prolonged survival . While these results strongly suggest that abnormal ERK1/2 activation contributes to the development of cardiomyopathy in LmnaH222P/H222P mice, its pathogenic role in affected skeletal muscles is unknown.
Based on our findings in heart, we hypothesize that abnormal activation of ERK1/2 is similarly involved in the pathogenesis of skeletal muscular dystrophy in the LmnaH222P/H222P mouse model of EDMD. In the present study, we demonstrate increased activation of ERK1/2 in affected skeletal muscle these mice. We further show that treatment with the MEK1/2 inhibitor selumetinib ameliorates pathological changes and improves function. These results suggest that MEK1/2 inhibitors may be beneficial in treating both cardiac and skeletal muscle disease in patients with EDMD.
LmnaH222P/H222P mice were bred and genotyped as previously described . Mice were fed chow and housed in a disease-free barrier facility with 12 h/12 h light/dark cycles. The Institutional Animal Care and Use Committee at Columbia University Medical Center approved the use of animals and the study protocols.
Drug treatment protocol and harvesting of muscle samples
Selumetinib (Selleck Chemicals) was dissolved in dimethyl sulfoxide (DMSO) (Sigma) at a concentration of 0.5 mg/mL to allow for intraperitoneal injections in mice. The placebo control consisted of the same volume of DMSO. Selumetinib was delivered at a dose of 1 mg/kg daily by intraperitoneal injection using a 27 5/8-gauge syringe starting when mice were 16 weeks of age and continuing until 20 weeks of age. At the end of the study, mice were sacrificed and hindlimb and diaphragm muscles dissected. Part of each dissected muscle was frozen in liquid nitrogen and stored at -80°C for biochemical analysis. The remaining muscle was rapidly frozen in isopentane pre-chilled by liquid nitrogen for cryostat sectioning.
Frozen pieces of quadriceps femoris, diaphragm, and tibialis anterior were mounted in Tissue-Tek (Fisher Scientific) and 10 μm sections cut on a cryostat. Sections were stained with hematoxylin and eosin for histological analysis. Representative sections were photographed using a Microphot SA (Nikon) light microscope attached to a Spot RT Slide camera (Diagnostic Instruments). Images were processed using Adobe Photoshop CS (Adobe Systems).
Osmotic shock of C2C12 cells stably expression wild-type and H222P lamin A
Generation of stable C2C12 cells expressing wild-type and H222P lamin A has been described previously . These cells were maintained at 37°C with 5% CO2 and subcultured at approximately 60% to 70% confluence in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum (Invitrogen). To assess the impact of osmotic shock on the activation of ERK1/2, cells were treated with D-sorbitol (600 mM) for 1 h and proteins were harvested in RIPA extraction buffer (Cell Signaling Technology) as previously described .
Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR)
Total RNA was extracted using the RNeasy isolation kit (Qiagen). Total RNA was used to synthesize cDNA using SuperScript First-strand Synthesis System (Invitrogen) according to the manufacturer’s instructions. For each replicate in each experiment, RNA from tissue samples of different animals was used. Primers were designed corresponding to mouse RNA sequences using Primer3 . Real-time quantitative RT-PCR reactions contained HotStart-IT SYBR green qPCR Master Mix (Affymetrix), 200 nM of each primer and 0.2 μL of template in a reaction volume of 25 μL. Amplification was carried out using the ABI 7300 Real-time PCR System (Applied Biosystems). Relative levels of mRNA expression were calculated using the ΔΔCT method  and individual expression values were normalized by comparison to Gapdh mRNA.
Protein extraction and immunoblotting
Skeletal muscle was homogenized in RIPA extraction buffer (Cell Signaling Technology) as previously described . Extracted proteins were separated by SDS-polyacrylamide gel electrophoresis, transferred to nitrocellulose membranes, and blotted with primary antibodies against ERK1/2 and phosphorylated ERK1/2 (Cell Signaling Technology). Secondary antibodies were horseradish peroxidate-conjugated (GE Healthcare). Recognized proteins were visualized by enhanced chemiluminescence (GE Healthcare). To quantify results, the immunoblots were scanned and band densities calculated using ImageJ64 (Applied Imaging). Signals obtained for phosphorylated ERK1/2 were normalized to those for total ERK1/2.
Serum was separated from mouse blood and stored at -80°C for 3 to 9 months until analyzed. Creatine phosphokinase (CPK) and aspartate aminotransferase (AST) activities were measured using an Analyst III Analyzer (Hemagen Diagnostics) in the Comparative Pathology Laboratory at Columbia University Medical Center. CPK and AST activities have been shown to be stable in rodent serum stored for up to 360 days at -70°C .
Limb grip strength measurements
LmnaH222P/H222P mice treated with DMSO or selumetinib were subjected to limb grip strength testing using a horizontally positioned grip strength meter (Bioseb). Mice were lowered by the tail towards the grid on the apparatus. Upon grasping the grid with their limbs, mice were pulled backward in the horizontal plane. The procedure was repeated consecutively three times and the peak tension of the three pulls was recorded as the grip strength value. Each animal was subjected to a total of two serial trials of three pulls each with 20 s of rest in between.
Values for real-time quantitative RT-PCR, scanned immunoblots, internalized nuclei, serum CPK and AST activities, and grip strength were compared using an unpaired Student t-tests. Values for Feret’s diameter were compared using two-way ANOVA. Statistical analyses were performed using Prism (GraphPad Software).
Results and discussion
Dystrophic skeletal muscle pathology in LmnaH222P/H222Pmice
Abnormal ERK1/2 signaling in skeletal muscle of LmnaH222P/H222Pmice
Stress-induced activation of ERK1/2 in cultured myoblasts stably expressing H222P lamin A
Blocking ERK1/2 activity with selumetinib has beneficial effects on skeletal muscle in LmnaH222P/H222Pmice
We have shown increased activity of ERK1/2 in skeletal muscle of the LmnaH222P/H222P mouse model of autosomal EDMD and that blocking its activity ameliorates pathology. These results are in accordance with a growing body of research providing evidence that alterations in various cellular signaling pathways, including ERK1/2, are involved in the pathogenesis of muscular dystrophy . In addition to autosomal EDMD, ERK1/2 has been implicated as contributing to skeletal or cardiac muscle pathology in mdx[39–41], γ-sarcoglycan-deficient [42, 43], and Lama2Dy-w mice, respective small animal models of Duchenne, limb girdle type 2C, and a form of congenital muscular dystrophy. ERK1/2 activity is also abnormally increased in hearts of mice with emerin deficiency, which is the genetic alteration in X-linked EDMD .
Blocking increased ERK1/2 signaling activity with selumetinib had beneficial effects on skeletal muscle function in LmnaH222P/H222P mice. Previously, we obtained similar results with respect to the cardiomyopathy that occurs in these mice [24–27]. In a human clinical trial, selumetinib has been reported to promote muscle gain in patients with cholangiocarcinoma . As oral selumetinib and other orally bioavailable MEK1/2 inhibitors with encouraging safety profiles are currently in clinical development for other indications [47, 48], pilot trials in patients with EDMD and possibly other muscular dystrophies should be considered.
Emery-Dreifuss muscular dystrophy
Extracellular signal-regulated kinase
Lamin A/C gene
Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase
Reverse transcription-polymerase chain reaction.
We thank Dr. Gisèle Bonne (Institut de Myologie) for providing LmnaH222P/H222P mice and Dr. Michio Hirano (Columbia University) for assistance with grip strength testing. This work was supported by grants from the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR048997) and Los Angeles Thoracic and Cardiovascular Foundation to HJW and a grant from the Association Franaçise Contre les Myopathies to AM.
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