Characterization of the FHL protein family

Funded Activity Summary

Skeletal muscle responds to exercise or mechanical load, in a process known as hypertrophy. Hypertrophy is initiated by a population of immature muscle cells known as myoblasts which fuse to form myotubes, and then mature to form muscle fibers (differentiation). Many proteins involved in a cascade of activation and-or deactivation are important for regulating hypertrophy (hypertrophic signaling). Failure of skeletal muscle to induce hypertrophy can lead to muscle degeneration. The FHL proteins are highly expressed in skeletal muscle. FHL proteins are molecular scaffolds which direct assembly of protein complexes to form the muscle contraction machinery (sarcomere). We propose FHL proteins will initiate-regulate skeletal muscle hypertrophy. Increased levels of FHL1 correlate with skeletal muscle hypertrophy. However, it is unclear if increased FHL1 is alone sufficient to induce hypertrophy directly. We have genetically engineered mice to express elevated levels of FHL1 specifically in skeletal muscles (FHL1 transgenic mice) and these mice show muscle enlargement. FHL1 transgenic mice have larger muscle fibers and are >7-fold stronger than non-transgenic littermates. We are currently examining which cell signaling pathways are affected by elevated FHL1. We are also investigating the role of another family member FHL3 in the differentiation of immature myoblasts, a process essential for both embryonic and postnatal skeletal muscle (hypertrophy) development. In the cell nucleus, FHL2 regulates genes which control cell growth and death and increased nuclear levels of FHL2 been detected in prostate cancer biopsies. Recently we demonstrated that FHL2 binds and is sequestered from the nucleus, by a protein, filamin. We are investigating the FHL2-mediated regulation of genes in human melanoma cells, which due to gene mutation are devoid of filamin and will determine how this affects FHL2 function in muscle.

Funded Activity Details

Start Date: 01-01-2007

End Date: 01-01-2009

Funding Scheme: NHMRC Project Grants

Funding Amount: $517,960.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Neurosciences not elsewhere classified

ANZSRC Socio-Economic Objective (SEO)

There are no SEO codes available for this funding activity

Other Keywords

cell differentiation | gene knockout | hypertrophy | muscle | muscle atrophy | muscle development | musculoskeletal | nuclear-cytoplasmic transport | skeletal muscle | transcriptional regulation

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