Dhanarajan Rajakumar1, Senthilnathan Senguttuvan2, Mathew Alexander3, Anna Oommen4. 1. Section of Neurochemistry, Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India. Electronic address: dhanurajan@hotmail.com. 2. Center for Stem Cell Research, Christian Medical College, Vellore, Tamil Nadu, India. 3. Section of Neurology, Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India. 4. Section of Neurochemistry, Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India.
Abstract
AIMS: Dysferlinopathies are autosomal recessive neuromuscular disorders arising from mutations of the protein dysferlin that preferentially affect the limbs which waste and weaken. The pathomechanisms of the diseases are not known and effective treatment is not available. Although free radicals and upstream signaling by the redox sensitive transcription factor, NF-κB, in activation of the ubiquitin pathway are shown to occur in several muscle wasting disorders, their involvement in dysferlinopathy is not known. This study analyzed the role of oxidative stress, NF-κB and the ubiquitin pathway in dysferlinopathic muscle and in dysferlin knockdown human myoblasts and myotubes. MAIN METHODS: Fourteen dysferlinopathic muscle biopsies and 8 healthy control muscle biopsies were analyzed for oxidative stress, NF-κB activation and protein ubiquitinylation and human primary myoblasts and myotubes knocked down for dysferlin were studied for their state of oxidative stress. KEY FINDINGS: Dysferlinopathic muscle biopsies showed NF-κB p65 signaling induced protein ubiquitinylation in response to oxidative stress. Dysferlin knock down primary muscle cell cultures confirmed that oxidative stress is induced in the absence of dysferlin in muscle. SIGNIFICANCE: Anti-oxidants that also inhibit nitrosative stress and NF-κB activation, might prove to be of therapeutic benefit in slowing the progression of muscle wasting that occurs with dysferlinopathy.
AIMS: Dysferlinopathies are autosomal recessive neuromuscular disorders arising from mutations of the protein dysferlin that preferentially affect the limbs which waste and weaken. The pathomechanisms of the diseases are not known and effective treatment is not available. Although free radicals and upstream signaling by the redox sensitive transcription factor, NF-κB, in activation of the ubiquitin pathway are shown to occur in several muscle wasting disorders, their involvement in dysferlinopathy is not known. This study analyzed the role of oxidative stress, NF-κB and the ubiquitin pathway in dysferlinopathic muscle and in dysferlin knockdown human myoblasts and myotubes. MAIN METHODS: Fourteen dysferlinopathic muscle biopsies and 8 healthy control muscle biopsies were analyzed for oxidative stress, NF-κB activation and protein ubiquitinylation and human primary myoblasts and myotubes knocked down for dysferlin were studied for their state of oxidative stress. KEY FINDINGS:Dysferlinopathic muscle biopsies showed NF-κB p65 signaling induced protein ubiquitinylation in response to oxidative stress. Dysferlin knock down primary muscle cell cultures confirmed that oxidative stress is induced in the absence of dysferlin in muscle. SIGNIFICANCE: Anti-oxidants that also inhibit nitrosative stress and NF-κB activation, might prove to be of therapeutic benefit in slowing the progression of muscle wasting that occurs with dysferlinopathy.
Authors: Vanessa R Haynes; Stacey N Keenan; Jackie Bayliss; Erin M Lloyd; Peter J Meikle; Miranda D Grounds; Matthew J Watt Journal: J Lipid Res Date: 2019-06-15 Impact factor: 5.922
Authors: Paz García-Campos; Ximena Báez-Matus; Carlos Jara-Gutiérrez; Marilyn Paz-Araos; César Astorga; Luis A Cea; Viviana Rodríguez; Jorge A Bevilacqua; Pablo Caviedes; Ana M Cárdenas Journal: Int J Mol Sci Date: 2020-06-16 Impact factor: 5.923