GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy

Cozzoli, Anna; Capogrosso, Roberta Francesca; Sblendorio, Valeriana; Dinardo, Maria Maddalena; Jagerschmidt, Catherine; Namour, Florence; Camerino, Claudia; A, De Luca

doi:10.1016/j.phrs.2013.03.003

Cited by 49 publications

(52 citation statements)

References 44 publications

(88 reference statements)

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“…The use of ND produced a significant increases in lean body and muscle mass as well as an improvement of physical activity in HIV-infected persons or in hemodialyzed patients [52, 53]. In rodent, ND has been shown to improve muscle wasting in the mdx mouse model of Duchenne muscular dystrophy [34]. Also in the HU rat, previous studies demonstrated that ND may be able to counterbalance Sol muscle atrophy induced by HU, although at doses higher than therapeutic ones [24].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, an histological analysis indicated an important role of ND in determining a decrease in the total area of muscle damage in the regenerating diaphragm of ND-treated mdx dystrophic mice. This result was attributed to a reduction in non-muscle area due to ND action [34, 66, 67]. Whether the effect of ND on Notch-1 and MyoD observed in HU mice is a prerequisite for or a consequence of the prevention of atrophy by the steroid remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…The Sol and EDL muscles were removed from the anesthetized mice and placed in NP solution for 30 minutes to equilibrate, as previously described [34]. The muscles were placed in a recording chamber at 27 ± 1°C.…”

Section: Methodsmentioning

confidence: 99%

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Effects of Nandrolone in the Counteraction of Skeletal Muscle Atrophy in a Mouse Model of Muscle Disuse: Molecular Biology and Functional Evaluation

et al. 2015

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Muscle disuse produces severe atrophy and a slow-to-fast phenotype transition in the postural Soleus (Sol) muscle of rodents. Antioxidants, amino-acids and growth factors were ineffective to ameliorate muscle atrophy. Here we evaluate the effects of nandrolone (ND), an anabolic steroid, on mouse skeletal muscle atrophy induced by hindlimb unloading (HU). Mice were pre-treated for 2-weeks before HU and during the 2-weeks of HU. Muscle weight and total protein content were reduced in HU mice and a restoration of these parameters was found in ND-treated HU mice. The analysis of gene expression by real-time PCR demonstrates an increase of MuRF-1 during HU but minor involvement of other catabolic pathways. However, ND did not affect MuRF-1 expression. The evaluation of anabolic pathways showed no change in mTOR and eIF2-kinase mRNA expression, but the protein expression of the eukaryotic initiation factor eIF2 was reduced during HU and restored by ND. Moreover we found an involvement of regenerative pathways, since the increase of MyoD observed after HU suggests the promotion of myogenic stem cell differentiation in response to atrophy. At the same time, Notch-1 expression was down-regulated. Interestingly, the ND treatment prevented changes in MyoD and Notch-1 expression. On the contrary, there was no evidence for an effect of ND on the change of muscle phenotype induced by HU, since no effect of treatment was observed on the resting gCl, restCa and contractile properties in Sol muscle. Accordingly, PGC1α and myosin heavy chain expression, indexes of the phenotype transition, were not restored in ND-treated HU mice. We hypothesize that ND is unable to directly affect the phenotype transition when the specialized motor unit firing pattern of stimulation is lacking. Nevertheless, through stimulation of protein synthesis, ND preserves protein content and muscle weight, which may result advantageous to the affected skeletal muscle for functional recovery.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of Nandrolone in the Counteraction of Skeletal Muscle Atrophy in a Mouse Model of Muscle Disuse: Molecular Biology and Functional Evaluation

et al. 2015

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“…In mdx mice, DT-200 improved running performance and increased diaphragm force 74 . DT-200 had positive phase 1 clinical data in healthy subjects 75 and has broad potential for multiple muscle wasting diseases.…”

Section: Promoting Muscle Massmentioning

confidence: 94%

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

Spinazzola

Kunkel

2016

Expert Opinion on Orphan Drugs

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Introduction Since the identification of the dystrophin gene in 1986, a cure for Duchenne muscular dystrophy (DMD) has yet to be discovered. Presently, there are a number of genetic-based therapies in development aimed at restoration and/or repair of the primary defect. However, growing understanding of the pathophysiological consequences of dystrophin absence has revealed several promising downstream targets for the development of therapeutics. Areas covered In this review, we discuss various strategies for DMD therapy targeting downstream consequences of dystrophin absence including loss of muscle mass, inflammation, fibrosis, calcium overload, oxidative stress, and ischemia. The rationale of each approach and the efficacy of drugs in preclinical and clinical studies are discussed. Expert opinion For the last 30 years, effective DMD drug therapy has been limited to corticosteroids, which are associated with a number of negative side effects. Our knowledge of the consequences of dystrophin absence that contribute to DMD pathology has revealed several potential therapeutic targets. Some of these approaches may have potential to improve or slow disease progression independently or in combination with genetic-based approaches. The applicability of these pharmacological therapies to DMD patients irrespective of their genetic mutation, as well as the potential benefits even for advanced stage patients warrants their continued investigation.

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“…Recently, the SARM GLPG0492 was tested in dystrophin-mutated mdx mouse preclinical models of DMD. GLPG0492 increased body weight, muscle mass and function in mdx mice that were either sedentary or were stressed by exercise (94). These data support the use of SARMs for the treatment of DMD either alone or as combination with exon-skipping drugs or other strategies such as NFkB or myostatin inhibitors.…”

Section: Potential Clinical Uses Of Sarmsmentioning

confidence: 99%

Development of selective androgen receptor modulators (SARMs)

Narayanan

Coss

Dalton

2018

Molecular and Cellular Endocrinology

187

139

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The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits.

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GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy

Cited by 49 publications

References 44 publications

Effects of Nandrolone in the Counteraction of Skeletal Muscle Atrophy in a Mouse Model of Muscle Disuse: Molecular Biology and Functional Evaluation

Effects of Nandrolone in the Counteraction of Skeletal Muscle Atrophy in a Mouse Model of Muscle Disuse: Molecular Biology and Functional Evaluation

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

Development of selective androgen receptor modulators (SARMs)

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