Atrophy of skeletal muscle is a debilitating response to denervation, disuse, fasting, glucocorticoids, many systemic diseases (e.g. cancer cachexia, renal failure) and aging. We showed that these various types of rapid atrophy result primarily from accelerated protein breakdown, triggered by the activation of the FoxO transcription factors and alterations in the expression of a set of about 80 atrophy-related genes ("atrogenes"), including two muscle-specific ubiquitin ligases, MuRF1 and atrogin-1/MAFbx, whose dramatic induction is essential for rapid wasting. To understand the atrophy process, it will be important to learn more about MuRF1's function and cofactors in vivo and to identify the muscle proteins that MuRF1 targets for degradation during atrophy. We have identified new protein partners of MuRF1 (S5a and novel E2s) that enhance MuRF1- dependent proteolysis in vitro and protein substrates (including critical myofibrillar components) that are lost selectively during denervation atrophy. Their precise roles in the atrophy process will be elucidated. Although the accelerated proteolysis during atrophy is due primarily to activation of the ubiquitin-proteasome pathway, we recently found that FoxO3, denervation, and fasting also stimulate lysosomal proteolysis and autophagy by enhancing transcription of many autophagy-related (atg) genes. We hope to clarify how autophagy is activated and the relative importance of the autophagic and proteasomal pathways in the destruction of different muscle components, especially in the loss of mitochondria and myofibrillar proteins, during atrophy in vivo. To obtain a fuller understanding of the transcriptional changes during atrophy, we plan to use improved gene microarray technology to identify the complete set of atrogenes upregulated and down regulated similarly in various types of atrophy. These studies should also enable us to define the specific roles in activating these transcriptional changes of the three FoxO family members (FoxO1, 3, and 4) and of NFkB, which is also critical for atrophy. We hope to learn how these transcription factors influence atrogene expression, proteolysis, and cell mass and their importance in vivo in the atrophy induced by glucocorticoids, fasting, and denervation. We recently found that expression of the exercise-induced transcriptional coactivator, PGC-11, and its homolog, PGC-12 fall dramatically during various types of atrophy, but that maintaining PGC-11 expression at high levels inhibits the induction of atrogin-1 and MuRF1 and blocks atrophy. A major goal will be to elucidate the mechanisms by which PGC-11 normally inhibits atrogene expression and protein loss and is repressed during atrophy, and to learn whether PGC12 serves similar functions in preserving muscle mass.
The overall goal of the various studies described in this grant application is to clarify the biochemical and transcriptional mechanisms responsible for the accelerated protein degradation that causes the rapid atrophy of skeletal muscles with disuse or nerve injury and in various systemic diseases (e.g. cancer, sepsis, renal failure) and aging.
|Piccirillo, Rosanna; Demontis, Fabio; Perrimon, Norbert et al. (2014) Mechanisms of muscle growth and atrophy in mammals and Drosophila. Dev Dyn 243:201-15|
|Lee, Donghoon; Goldberg, Alfred L (2013) SIRT1 protein, by blocking the activities of transcription factors FoxO1 and FoxO3, inhibits muscle atrophy and promotes muscle growth. J Biol Chem 288:30515-26|
|Demontis, Fabio; Piccirillo, Rosanna; Goldberg, Alfred L et al. (2013) Mechanisms of skeletal muscle aging: insights from Drosophila and mammalian models. Dis Model Mech 6:1339-52|
|Bhutani, Nidhi; Piccirillo, Rosanna; Hourez, Raphael et al. (2012) Cathepsins L and Z are critical in degrading polyglutamine-containing proteins within lysosomes. J Biol Chem 287:17471-82|
|Menzies, Fiona M; Hourez, Raphael; Imarisio, Sara et al. (2010) Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy. Hum Mol Genet 19:4573-86|
|Altun, Mikael; Besche, Henrike C; Overkleeft, Herman S et al. (2010) Muscle wasting in aged, sarcopenic rats is associated with enhanced activity of the ubiquitin proteasome pathway. J Biol Chem 285:39597-608|
|Brault, Jeffrey J; Jespersen, Jakob G; Goldberg, Alfred L (2010) Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. J Biol Chem 285:19460-71|
|Uchiki, Tomoaki; Kim, Hyoung Tae; Zhai, Bo et al. (2009) The ubiquitin-interacting motif protein, S5a, is ubiquitinated by all types of ubiquitin ligases by a mechanism different from typical substrate recognition. J Biol Chem 284:12622-32|
|Cohen, Shenhav; Brault, Jeffrey J; Gygi, Steven P et al. (2009) During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. J Cell Biol 185:1083-95|
|Zhao, Jinghui; Brault, Jeffrey J; Schild, Andreas et al. (2008) Coordinate activation of autophagy and the proteasome pathway by FoxO transcription factor. Autophagy 4:378-80|
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