Together, these data demonstrate how oxidative modifications on actin promote muscle weakness in RA patients and provide novel leads for targeted therapeutic treatment to improve muscle function.
The mutation decreased also the amount of the myosin heads which bound strongly to actin at high Ca<sup>2+</sup> and increased the number of these heads at relaxation; this may contribute to contractures and muscle weakness.
Hence, we used a transgenic mouse model expressing a well-described D286G mutant skeletal muscle α-actin protein and recapitulating the human condition of contractile deregulation and severe skeletal muscle weakness.
Using a mouse model of DM1 (HSA(LR)), we found that CUG repeats in the 3' untranslated region (UTR) of human skeletal actin increase active GSK3β in skeletal muscle of mice, prior to the development of skeletal muscle weakness.
We show that four of the mutations cause changes in affinity for actin, which may cause muscle weakness in these patients, whereas two show defective Ca2+ activation of contractility.
Mutations in actin and tropomyosin, identified in patients with myopathic disease have been used in tissue culture models and functional studies with a view to understand how these mutations impact on skeletal muscle structure and function and result in muscle weakness.
Our findings indicate that the presence of muscle weakness and hypotonia in patients may be associated with the dysregulated gene activities of cell motility, muscle contraction and development, actin binding, and cytoskeletal-related activities.
Mutations in human alpha-skeletal actin have been implicated in causing congenital nemaline myopathy, a disease characterized histopathologically by nemaline bodies in skeletal muscle and manifested in the patient as skeletal muscle weakness.
It is suggested that the R133W beta-Tm mutation induces alteration in myosin-actin kinetics causing a reduced number of myosin molecules in the strong actin-binding state, resulting in overall muscle weakness in the absence of muscle wasting.
Data from our tissue culture and Drosophila models show that the Val163Met mutation in alpha-skeletal actin can affect the dynamics of other actin isoforms and severely disrupt sarcomeric structure, processes that can contribute to muscle weakness.
In vitro motility studies indicate that abnormal interactions between actin and tropomyosin are the likely principal cause of muscle weakness for D292V, with tropomyosin stabilized in the "switched off" position.