Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures

Autor: Cynthia J. Balog-Alvarez, Mihye Ahn, Robert W. Grange, Kathryn R. Wagner, Candice Brinkmeyer-Langford, Carl Morris, Daniel J. Bogan, Martin Styner, Hongtu Zhu, Joe N. Kornegay, Leigh C. Warsing, Steven W. Cotten, Naili Liu, Jiahui Wang, Jennifer L. Dow, Janet R. Bogan, Joe Palandra, Monte S. Willis, Zheng Fan
Rok vydání: 2016
Předmět:
0301 basic medicine
Activin Receptors
Type II
Myostatin
Quadriceps Muscle
Muscle hypertrophy
Animals
Genetically Modified
Dystrophin
Contractures
0302 clinical medicine
Orthopedics and Sports Medicine
Muscular dystrophy
Gait
Whippets
Golden retriever muscular dystrophy (GRMD)
Myostatin inhibition
Sartorius muscle
PAX7 Transcription Factor
musculoskeletal system
Magnetic Resonance Imaging
Biomechanical Phenomena
Phenotype
medicine.symptom
medicine.medical_specialty
Contracture
Satellite Cells
Skeletal Muscle
Posture
Biology
03 medical and health sciences
Dogs
Atrophy
Internal medicine
medicine
Animals
Genetic Predisposition to Disease
Muscle Strength
Molecular Biology
Muscle contracture
Research
Cell Biology
Muscular Dystrophy
Animal
medicine.disease
Disease Models
Animal
030104 developmental biology
Endocrinology
biology.protein
Hybridization
Genetic
Joints
030217 neurology & neurosurgery
Zdroj: Skeletal Muscle
ISSN: 2044-5040
DOI: 10.1186/s13395-016-0085-7
Popis: Background Myostatin (Mstn) is a negative regulator of muscle growth whose inhibition promotes muscle growth and regeneration. Dystrophin-deficient mdx mice in which myostatin is knocked out or inhibited postnatally have a less severe phenotype with greater total mass and strength and less fibrosis and fatty replacement of muscles than mdx mice with wild-type myostatin expression. Dogs with golden retriever muscular dystrophy (GRMD) have previously been noted to have increased muscle mass and reduced fibrosis after systemic postnatal myostatin inhibition. Based partly on these results, myostatin inhibitors are in development for use in human muscular dystrophies. However, persisting concerns regarding the effects of long-term and profound myostatin inhibition will not be easily or imminently answered in clinical trials. Methods To address these concerns, we developed a canine (GRippet) model by crossbreeding dystrophin-deficient GRMD dogs with Mstn-heterozygous (Mstn+/−) whippets. A total of four GRippets (dystrophic and Mstn+/−), three GRMD (dystrophic and Mstn wild-type) dogs, and three non-dystrophic controls from two litters were evaluated. Results Myostatin messenger ribonucleic acid (mRNA) and protein levels were downregulated in both GRMD and GRippet dogs. GRippets had more severe postural changes and larger (more restricted) maximal joint flexion angles, apparently due to further exaggeration of disproportionate effects on muscle size. Flexors such as the cranial sartorius were more hypertrophied on magnetic resonance imaging (MRI) in the GRippets, while extensors, including the quadriceps femoris, underwent greater atrophy. Myostatin protein levels negatively correlated with relative cranial sartorius muscle cross-sectional area on MRI, supporting a role in disproportionate muscle size. Activin receptor type IIB (ActRIIB) expression was higher in dystrophic versus control dogs, consistent with physiologic feedback between myostatin and ActRIIB. However, there was no differential expression between GRMD and GRippet dogs. Satellite cell exhaustion was not observed in GRippets up to 3 years of age. Conclusions Partial myostatin loss may exaggerate selective muscle hypertrophy or atrophy/hypoplasia in GRMD dogs and worsen contractures. While muscle imbalance is not a feature of myostatin inhibition in mdx mice, findings in a larger animal model could translate to human experience with myostatin inhibitors. Electronic supplementary material The online version of this article (doi:10.1186/s13395-016-0085-7) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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