Treatment Of Muscle Wasting Research Articles

Glycogen Synthase Kinase 3β negatively regulates myogenic differentiation

Glycogen Synthase Kinase 3β (GSK-3β) has been implicated in the negative regulation of both cardiac and skeletal muscle hypertrophy. Recently we showed that pharmacological inactivation of GSK-3β is sufficient to stimulate myogenic differentiation. To further investigate the role of GSK-3β in this process, GSK-3β expression was suppressed in C2C12 myoblasts by RNA interference, which resulted in increased Muscle Creatine Kinase (MCK) activity after 3 days of differentiation. In addition, myogenic conversion of Mouse Embryonic Fibroblasts (MEF) by over-expression of the muscle transcription factor MyoD resulted in enhanced transactivation of a co-transfected Troponin-I promoter-reporter construct in GSK-3β-/- compared to WT MEFs. Furthermore, transient transfection of GSK-3β-/- MEFs with a GSK-3β expression construct reduced Troponin-I promoter transactivation, whereas co-transfection of a kinase inactive variant (K85R) of GSK-3β did not affect increased myogenic conversion of GSK-3β-/- MEFs. This implies that GSK-3β kinase activity is required for its negative regulatory role in myogenic differentiation. Therefore inactivation of GSK-3β can have a potential therapeutical role in prevention or treatment of muscle wasting. This abstract was sponsored by the Netherlands Asthma Foundation (320263).

Modulating skeletal muscle mass by postnatal, muscle-specific inactivation of the myostatin gene.

By using a conditional gene targeting approach exploiting the cre-lox system, we show that postnatal inactivation of the myostatin gene in striated muscle is sufficient to cause a generalized muscular hypertrophy of the same magnitude as that observed for constitutive myostatin knockout mice. This formally demonstrates that striated muscle is the production site of functional myostatin and that this member of the TGFbeta family of growth and differentiation factors regulates muscle mass not only during early embryogenesis but throughout development. It indicates that myostatin antagonist could be used to treat muscle wasting and to promote muscle growth in man and animals.

Identification of Ankrd2, a Novel Skeletal Muscle Gene Coding for a Stretch-Responsive Ankyrin-Repeat Protein

Mechanically induced hypertrophy of skeletal muscles involves shifts in gene expression leading to increases in the synthesis of specific proteins. Full characterization of the regulation of muscle hypertrophy is a prerequisite for the development of novel therapies aimed at treating muscle wasting (atrophy) in human aging and disease. Using suppression subtractive hybridization, cDNAs corresponding to mRNAs that increase in relative abundance in response to mechanical stretch of mouse skeletal muscles in vivo were identified. A novel 1100-bp transcript was detected exclusively in skeletal muscle. This exhibited a fourfold increase in expression after 7 days of stretch. The transcript had an open reading frame of 328 amino acids encoding an ATP/GTP binding domain, a nuclear localization signal, two PEST protein-destabilization motifs, and a 132-amino-acid ankyrin-repeat region. We have named this gene ankyrin-repeat domain 2 (stretch-responsive muscle) (Ankrd2). We hypothesize that Ankrd2 plays an important role in skeletal muscle hypertrophy.