Aberrations in Energetic Metabolism and Stress-Related Pathways Contribute to Pathophysiology in the Neb Conditional Knockout Mouse Model of Nemaline Myopathy.
Study found that adult nebulin-deficient mice displayed severe muscle atrophy and weakness in vivo related to a low nebulin content but an improved fatigue resistance due to a slower contractile phenotype.
To study the functions of nebulin's C-terminus we generated a mouse model deleting the final two unique C-terminal domains the serine-rich region (SRR) and the SH3 domain (NebDelta163-165).
Muscle fibers are weak in the absence of Neb in particular when large tension develops which may structurally damage the thin filament when Neb is absent.
Pnn downregulation in skeletal muscle causes a muscular dystrophic phenotype associated with NEB deficiency and the CCD domain is incapable of replacing full length Pnn in terms of functional capacity.
The functional roles of nebulin extend beyond thin filament length regulation and include roles in maintaining physiological Z-disk widths and myofibrillar connectivity.
These results indicate that in the absence of nebulin the attachment probability of the myosin motors to actin is decreased revealing a direct role for nebulin in promoting strong actomyosin interactions responsible for force and power production.
NEB is essential for active stress production maintenance of functional integrity during cyclic activation and length-tension properties consistent with a role in specifying normal thin filament length
Speed of Ca(2+) uptake was >3-fold decreased in sarcoplasmic reticulum vesicles isolated from nebulin-free muscle as well as in nebulin-free intact myofibers.
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