Genetic deletion of muscle RANK or selective inhibition of RANKL is not as effective as full-length OPG-fc in mitigating muscular dystrophy
© The Author(s). 2018
Received: 8 March 2018
Accepted: 10 April 2018
Published: 24 April 2018
Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that regulates synchronously bone and skeletal muscle physiopathology is still elusive. Receptor-activator of nuclear factor κB (RANK), its ligand RANKL and the soluble decoy receptor osteoprotegerin (OPG) are the key regulators of osteoclast differentiation and bone remodelling. We thus hypothesized that RANK/RANKL/OPG, which is a key pathway for bone regulation, is involved in Duchenne muscular dystrophy (DMD) physiopathology. Our results show that muscle-specific RANK deletion (mdx-RANK mko ) in dystrophin deficient mdx mice improves significantly specific force [54% gain in force] of EDL muscles with no protective effect against eccentric contraction-induced muscle dysfunction. In contrast, full-length OPG-Fc injections restore the force of dystrophic EDL muscles [162% gain in force], protect against eccentric contraction-induced muscle dysfunction ex vivo and significantly improve functional performance on downhill treadmill and post-exercise physical activity. Since OPG serves a soluble receptor for RANKL and as a decoy receptor for TRAIL, mdx mice were injected with anti-RANKL and anti-TRAIL antibodies to decipher the dual function of OPG. Injections of anti-RANKL and/or anti-TRAIL increase significantly the force of dystrophic EDL muscle [45% and 17% gains in force, respectively]. In agreement, truncated OPG-Fc that contains only RANKL domains produces similar gains, in terms of force production, than anti-RANKL treatments. To corroborate that full-length OPG-Fc also acts independently of RANK/RANKL pathway, dystrophin/RANK double-deficient mice were treated with full-length OPG-Fc for 10 days. Dystrophic EDL muscles exhibited a significant gain in force relative to untreated dystrophin/RANK double-deficient mice, indicating that the effect of full-length OPG-Fc is in part independent of the RANKL/RANK interaction. The sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) activity is significantly depressed in dysfunctional and dystrophic muscles and full-length OPG-Fc treatment increased SERCA activity and SERCA-2a expression. These findings demonstrate the superiority of full-length OPG-Fc treatment relative to truncated OPG-Fc, anti-RANKL, anti-TRAIL or muscle RANK deletion in improving dystrophic muscle function, integrity and protection against eccentric contractions. In conclusion, full-length OPG-Fc represents an efficient alternative in the development of new treatments for muscular dystrophy in which a single therapeutic approach may be foreseeable to maintain both bone and skeletal muscle functions.
Bone and muscle have the ability to adjust their structures to meet their mechanical, hormonal, and metabolic environments. Osteoporosis and muscle atrophy/dysfunction occur simultaneously in a number of conditions, including spaceflight, extended bed rest, and several muscular and neuromuscular diseases. Local and systemic alterations in hormone and pro-inflammatory cytokine levels stimulate muscle and bone atrophy [25, 32]. Changes in intracellular Ca2+ concentrations regulate the physiological activities and expression of specific bone and muscle genes [15, 30]. Poor bone health and increased incidence of bone factures are well recognized clinically in Duchenne muscular dystrophy (DMD) patients suggesting cross-talks and mutual cooperative interactions between bones and dystrophic muscles . However, the potential cellular and molecular mechanisms that may tie together bones and skeletal muscles during physiological and pathological conditions remain elusive.
The receptor-activator of nuclear factor κB ligand (RANKL), the membrane receptor RANK, and the soluble decoy receptor osteoprotegerin (OPG) are members of the tumor necrosis factor (TNF) superfamily that regulates bone remodelling [19, 27]. RANKL is expressed by osteoblasts, while RANK, its receptor, is expressed by pre-osteoclastic cells. The RANK/RANKL interaction induces the formation of multinucleated mature osteoclasts, ultimately causing bone resorption . OPG, the third protagonist, is also produced by osteoblasts, binds to RANKL and exerts an inhibitory effect on the pre-osteoclastic differentiation process . Structurally, the native OPG protein is highly conserved and contains four TNFR-like domains (RANKL binding sites), two death domains (tumour necrosis factor-related apoptosis-inducing ligand [TRAIL binding sites]), and a heparin-binding domain . Thus, OPG serves as a decoy receptor for the RANKL and TRAIL and is a very efficient anti-resorptive and anti-apoptotic agent .
The focus of research in our laboratory is to decipher the potential cellular and molecular mechanisms that may tie together bones and skeletal muscles during physiological and pathological conditions. We first hypothesized that RANK/RANKL/OPG pathway, a key regulator of bone homeostasis and Ca2+ storage, would contribute in the regulation of skeletal muscle integrity and function during the course of muscular dystrophy. We previously demonstrated that daily full-length OPG-Fc treatment markedly improved muscle function and integrity in 5 week-old mdx mice . The main objective of this study was to determine the specific contribution of muscle RANK, RANKL and TRAIL in muscular dystrophy. Using genetic and pharmacological approaches in young and adult dystrophic mice, we are able to show the unequivocal superior effects of full-length OPG-Fc in rescuing dystrophic muscles relative to selective muscle RANK deletion or anti-RANKL or anti-TRAIL treatments. Altogether, our results suggest that full-length OPG-Fc is a multifunctional protein that has the potential to impact on several different cellular processes with possibly profound implications for the treatment of DMD.
Materials and methods
Mice carrying the RANK floxed or RANK del alleles and muscle creatine kinase-cre (mck-cre) mice were backcrossed five times to a C57BL/6 background before generating the mck-cre RANK del/floxed (RANK mko ) mice as previously described [13, 20]. Male wild-type (C57BL/6) and mdx dystrophic mice (C57BL/10ScSn-Dmd mdx /J) were purchased from the Jackson Laboratory (Bar Harbor, ME, USA) and bred at our animal facility. RANK mko mice were also crossed with mdx-background mice to generate double deficient mice (dystrophin and RANK). Mice were screened for the desired genotype by PCR analysis. PCR products were amplified using primer pairs as listed in Additional file 1: Table S2. Dystrophic mdx mice were injected daily with full-length OPG-Fc  [i.p., 1 mg/kg/d R&D systems, MN, USA], PBS, anti-RANKL  [1 mg/kg/ every 3 d, clone IK22–5], anti-TRAIL  [1 mg/kg/every 3 d, clone H2B2] or truncated OPG-Fc [1 mg/kg/d, Syd Labs, MA, USA] from days 25 to 35 after birth. In another set of experiments, five six-month old mdx mice were injected daily, for 10 d, with full-length OPG-Fc [i.p. 1 mg/kg/d] followed by a downhill (eccentric) treadmill running protocol. C57BL/6 mice were used as a control and injected daily with the same volume of phosphate-buffered saline (vehicle). At the end of the experimental procedures, mice were euthanized by cervical dislocation under anesthesia and skeletal muscles [extensor digitorum longus (EDL), soleus (Sol) and diaphragm (Dia)] were removed and stored at − 80 °C for future analysis. All procedures were approved by the Université Laval Research Center Animal Care and Use Committee, based on the Canadian Council on Animal Care guidelines. All data generated or analysed during this study are included in this published article and its Additional file 1.
Immunofluorescence and staining
Transverse EDL muscle sections (10 μm) were cut (Leica Microsystems CM1850, Nussloch, Germany) in duplicate from the proximal and distal parts of the muscles. Tissue sections stained with hematoxylin and eosin (Sigma-Aldrich, St. Louis, MO, USA) were examined with an inverted microscope (Nikon, Ontario, Canada) and damage, regenerating and intact areas on approximately 100 myofibers per muscle were quantified with ImageJ software version 1.41 (National Institutes of Health, USA). The damaged area was defined as an area not occupied by normal or regenerating muscle fibers. Image series of EDL were taken using a confocal microscope (Axio Observer.Z1; Carl Zeiss, Germany) and acquired using a Quorum WaveFX spinning disc confocal system (Quorum Technologies, Ontario, Canada). Solid state laser lines 491 nm and 561 nm were used for excitation of green and red (Alexa-488 and Alexa-594), combined with appropriate BrightLine single-bandpass emission filters (536/40 nm and 624/40 nm, Semrock, NY, USA). z-series were acquired at the same time with DAPI fluorescence filter cube (Chroma Technology, VT, USA). The CCD camera used to capture the images was a Hamamatsu Image EM C-9100. Images were acquired and analyzed using Volocity software, version 4.2.1. Iterative restoration (deconvolution) was applied for the DAPI channel, using the same software.
Western blots and qPCR
Skeletal muscles were homogenized in a lysis buffer containing 1 μg/ml, protease inhibitor cocktail (P8340; Sigma-Aldrich, Ontario, Canada), 20 mM Tris-base pH 7.5, 140 mM NaCl, 1 mM MgCl2, 1 mM CaCl2, 10% glycerol, 1% Igepal (Sigma-Aldrich, Ontario, Canada), 2 mM Na3VO4, 8.3 mM NaF and 0.2 mM PMSF. The protein content of the supernatant was measured using BCA protein assay kit (EMD chemical, Nussloch Germany). Protein homogenates were electrophoretically separated on SDS-polyacrylamide gels, transferred to polyvinylidene difluoride membranes (PVDF; Bio-Rad, CA, USA), blocked in 5% skim milk and incubated overnight at 4°C with the following primary antibodies (all from Santa Cruz Biotechnology): anti-SERCA-1a, anti-SERCA-2a anti-RANK and anti-GAPDH. The membranes were washed and incubated with appropriate HRP-conjugated secondary antibodies (Santa Cruz Biotechnology, CA, USA). Bands were revealed using the ECL-Plus chemiluminescent detection system (Perkin-Elmer, MA, USA). Images of the membranes were acquired, scanned, and analyzed using Quantity One software (v4.6.6, Bio-Rad). For RT-PCR analysis (Additional file 1: Table S2), skeletal muscles were rapidly put in RNAlater RNA Stabilization Reagent (Qiagen, MD, USA). Total RNA was isolated using the RNeasy Fibrous Tissue Mini Kit (Qiagen, MD, USA) according to manufacturer’s instructions. During isolation process, RNA samples were treated with RNase-Free DNase Set (Qiagen, MD, USA). RNA quality was assessed using an Agilent 2100 Bioanalyzer (Agilent Technologies, CA, USA) and quantified using a NanoDrop 1000 Spectrophotometer (NanoDrop Technologies, DE, USA). The expression of the RANK gene in each sample was compared to the housekeeping gene GAPDH. Measurements were performed in duplicate for each standard and muscle sample.
Mice were injected with buprenorphine (i.p. 0.1 mg/kg) and were anaesthetized with pentobarbital sodium (i.p. 50 mg/kg) 15 min later. The right Sol and EDL muscles were resected and attached to a 305B-LR dual-mode lever arm system controlled by dynamic muscle control unit and data acquisition software (Aurora Scientific, Aurora, ON, Canada) as described by Dufresne et al. (2016) . For the eccentric contraction protocol, the muscles were set at optimal L0 and stimulated at 150 Hz for 700 ms. Five hundred ms into the stimulation protocol, the muscles were lengthened to 10% of L0 at 0.5 L0/s for 200 ms.
Downhill running protocol
Six month-old C57BL/6 and mdx mice were treated for 10 days with PBS (n = 12) or full-length OPG-Fc [1 mg/kg/d] (n = 12). From days 7 to 9, mice were trained for acclimatization on an horizontal (0% grade) motorized treadmill at 6, 8 and then 10 m/min for 5 min. Following the training protocol, mice ran on a downhill sloped (14-degree decline) at 10 m/min for 45 min. Mice were continually observed during the running protocol. Exhausted mice showing physical signs of discomfort were rested for 2 min. The running protocol was discontinued after 3 stops. Following the eccentric protocol, post-exercise mouse activity was measured by video tracking software in an open field for 24 h.
Frozen EDL, Sol and Dia muscles were homogenized with a ground-glass pestle in 5 volumes of 10 mM Tris/HCl (pH 8.3) supplemented with 0.3 M sucrose. SERCA activity was measured in A. R. Tupling’s laboratory with an assay adapted for a spectrophotometric plate reader according to Duhamel and colleagues (2007)  following the oxidation of NADH at 340 nm in assay buffer (pH 7.0) containing 1 mM EGTA, 10 mM phosphoenolpyruvate, 18 U/mL pyruvate kinase and lactate dehydrogenase, 0.2 mM NADH, 20 mM HEPES, 200 mM KCl, 15 mM MgCl2, 10 mM NaN3, and 5 mM ATP. The homogenized muscles and assay buffer were added to tubes containing 15 different concentrations of Ca2+ (between 7.6 and 4.7 pCa units) in the presence and absence of ionophore A23187 (4.2 μM). The absence of the ionophore causes back-inhibition of SERCA pumps. Then 0.3 mM NADH was added to start the reaction and the plate was read at a wavelength of 340 nm for 30 min at 37 °C. The different concentrations of Ca2+ were used to determine the maximal enzyme activity (Vmax) and pCa50. Lastly, cyclopiazonic acid (CPA; 40 μM), a highly specific SERCA inhibitor, was used to determine background activity.
All values are expressed as means +/− SEM. The data were analyzed with Student’s t-test or one-way ANOVA with Tukey post hoc test (InStat). The levels of significance was set at *p < 0.05, **p < 0.01, and ***p < 0.001 for PBS-treated mdx.
Results and discussion
OPG-fc is superior to muscle-specific RANK deletion in mitigating muscular dystrophy
Since full-length OPG-Fc was significantly more effective compared to muscle-specific RANK deletion in preserving muscle function during the most severe phase of degeneration in mdx mice, we next focused to determine the contribution of the different OPG domains to the preservation of muscle integrity (Fig. 2b). OPG is a soluble receptor for RANKL and a decoy receptor for TRAIL increasing cell survival by blocking the pro-apoptotic effects of the TRAIL/DR4–5 interaction [16, 33]. To determine the dual function of OPG and the implication of the RANKL and TRAIL domains, mdx mice were injected with anti-RANKL and anti-TRAIL antibodies (Fig. 2b). The inhibition of RANKL and TRAIL for 10 days increased the specific force production of dystrophic EDL muscles by 45% and 17%, respectively, which are markedly lower than full-length OPG-Fc treated mdx mice (162%) (Fig. 2c). Furthermore, the combination of anti-RANKL and anti-TRAIL was not superior to anti-RANKL treatment alone (Fig. 2c). To confirm the exclusive efficiency of full-length OPG-Fc, mdx mice were also treated with the truncated form of OPG-Fc that carries RANKL-binding domains (Fig. 2c). As expected, the truncated OPG-Fc had similar effects to anti-RANKL treatment, increasing by 48% the force production of dystrophic EDL muscles (Fig. 2c). To corroborate whether full-length OPG-Fc also acts independently of RANK/RANKL pathway, dystrophin/RANK double-deficient mice were treated with full-length OPG-Fc for 10 days. Dystrophic EDL muscles exhibited a significant gain in force (29%) relative to untreated dystrophin/RANK double-deficient mice, indicating that full-length OPG-Fc can act in part independently of the RANKL/RANK interaction (Fig. 2d). All treatments and muscle RANK deletion did not change muscle mass (Additional file 1: Table S1). Our results show that anti-RANKL, anti-TRAIL, truncated OPG-Fc treatments or RANK deletion are much less effective than full-length OPG-Fc against muscular dystrophy (Additional file 1: Figure S5).
Full length OPG-fc, but not muscle RANK deletion, prevents eccentric contraction-induced muscle dysfunction.
Full-length OPG-fc, but not muscle-specific RANK deletion, increases SERCA activity and expression in dystrophic EDL muscles
Perspective and conclusion
In the early 2000s, truncated OPG-Fc (AMGN-0007) reached clinical trial for the treatment of osteoporosis and bone metastasis [5, 7]. Truncated and full-length OPG-Fc can interact with RANKL preventing the downstream activation of NF-kB, a key controller of many genes involved in inflammation. Our observations that muscle-specific RANK deletion, anti-RANKL or truncated OPG-Fc and full-length OPG-Fc treatment protect fast-twitch fibers are of paramount importance, since these powerful fibers are the first to disappear in many forms of myopathies [28, 38]. However, we uncover a unique and superior role for full-length OPG-Fc in protecting muscle function and integrity in the mdx model of muscular dystrophy. Since full-length OPG-Fc rescues SERCA activity in fast-twitch dystrophic skeletal muscles, we anticipate that full-length OPG-Fc treatment would contribute to normalize SR Ca2+ regulation in muscular dystrophy by removing Ca2+ from the myoplasm and refilling the internal Ca2+ stores through the action of SERCA pumps. The stimulation of SERCA pumps should lead to better Ca2+ mobilization breaking the vicious cycle of muscle inflammation and Ca2+-dependent protease activation initiated by poor Ca2+ handling [9, 35].
We thank the Bioimaging platform at the CHU de Québec (CHUL), supported by the Canada Foundation for Innovation, for confocal analyses. We are indebted to Carlo Rago and Paul Kostenuik for providing over the years valuable information about DMD and OPG, respectively.
This work was supported by grants to JF from the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, Duchenne Alliance and Jesse’s Journey.
JF, SSD and JMP conceived the project and its design; SSD, ABP, SB, AA, DH, LM, VAF, DG, RT and HY performed experiments and data analysis; JF, SSD and AA wrote the manuscript; and all authors checked for scientific content and contributed to the final drafting of the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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