Involvement of oxidative stress, nuclear factor kappa B and the ubiquitin proteasomal pathway in dysferlinopathy.
OBJECTIVE
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.


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.


RESULTS
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.


CONCLUSIONS
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.
Section of Neurochemistry, Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India. Electronic address: dhanurajan@hotmail.com.
Dhanarajan
D
Rajakumar
Center for Stem Cell Research, Christian Medical College, Vellore, Tamil Nadu, India.
Senthilnathan
S
Senguttuvan
Section of Neurology, Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India.
Mathew
M
Alexander
Section of Neurochemistry, Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India.
Anna
A
Oommen
D000293:Adolescent; D000328:Adult; D002648:Child; D000073939:Dysferlin; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000503:physiopathology*; D032446:Myoblasts / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination; D055815:Young Adult
C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; D051996:Transcription Factor RelA; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
E3 ligase; Muscle wasting; NF-κBp65; Oxidative stress; Ubiquitin