Exercise Training Reverses Skeletal Muscle Atrophy in an Experimental Model of VCP Disease
Open accessAbstract
BACKGROUND: The therapeutic effects of exercise resistance and endurance training in the alleviation of muscle hypertrophy/atrophy should be considered in the management of patients with advanced neuromuscular diseases. Patients with progressive neuromuscular diseases often experience muscle weakness, which negatively impact independence and quality of life levels. Mutations in the valosin containing protein (VCP) gene lead to Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) and more recently affect 2% of amyotrophic lateral sclerosis (ALS)-diagnosed cases. METHODS/PRINCIPLE FINDINGS: The present investigation was undertaken to examine the effects of uphill and downhill exercise training on muscle histopathology and the autophagy cascade in an experimental VCP mouse model carrying the R155H mutation. Progressive uphill exercise in VCP(R155H/+) mice revealed significant improvement in muscle strength and performance by grip strength and Rotarod analyses when compared to the sedentary mice. In contrast, mice exercised to run downhill did not show any significant improvement. Histologically, the uphill exercised VCP(R155H/+) mice displayed an improvement in muscle atrophy, and decreased expression levels of ubiquitin, P62/SQSTM1, LC3I/II, and TDP-43 autophagy markers, suggesting an alleviation of disease-induced myopathy phenotypes. There was also an improvement in the Paget-like phenotype. CONCLUSIONS: Collectively, our data highlights that uphill exercise training in VCP(R155H/+) mice did not have any detrimental value to the function of muscle, and may offer effective therapeutic options for patients with VCP-associated diseases.
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Muscle from IBMPFD patients carrying VCP mutations and transgenic mice expressing VCP mutants display accumulations of SQSTM1- and LC3-positive autophagosomes and abnormal mitochondria.
“muscle from IBMPFD patients carrying VCP mutations [246] and transgenic mice expressing VCP mutants [244,248,249] display accumulations of SQSTM1- and LC3-positive autophagosomes and abnormal mitochondria [250,251].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [250]
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- Authors
- Nalbandian, A., Nguyen, C., Katheria, V., Llewellyn, K. J., Badadani, M., Caiozzo, V., & Kimonis, V. E.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Kimonis, Virginia E.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-10-09
- Volume
- 8
- Issue
- 10
- Pages
- e76187
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3794032
- OpenAlex
- W2012831734
- Cited by
- 30
- References
- 45
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 5 · 2016: 2 · 2015: 4 · 2014: 2
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Muscular Dystrophy Association (175682)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- VCP, skeletal muscle atrophy, exercise training, uphill running, downhill running, autophagy, ubiquitin, p62, LC3, TDP-43, muscle strength, neuromuscular disorders, mouse model
- MeSH terms
- Valosin Containing Protein, Adenosine Triphosphatases, Animals, Autophagy, Disease Models, Animal, Mitochondria, Muscular Atrophy, Mutation, Phenotype, Physical Conditioning, Animal, Apoptosis, Muscle, Skeletal, Cell Cycle Proteins, Mice, Muscle Strength
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