Skeletal muscle atrophy is a widespread physiological phenomenon and significant health problem associated with muscle disuse (immobilization, bedrest, denervation) and various diseases (cancer, sepsis, AIDS, diabetes, chronic heart failure, chronic obstructive pulmonary disease). However, our understanding of the signaling molecules that regulate muscle mass during an atrophy condition are ill defined. Therefore the long- range goal of our research program is to understand the regulation of signaling pathways that cause muscle atrophy during various conditions. Eventually improved understanding will lead to the identification of the most suitable targets for specific interventions. One family of proteins that is known to cause skeletal muscle atrophy is the FOXO family, and FOXO signaling is increased in a variety of atrophy conditions, including cast immobilization, sepsis, cancer and starvation. However, our understanding of the regulation of FOXO signaling in skeletal muscle is largely confined to the phosphorylation of FOXO factors via the IGF1/PI3K/Akt pathway. While this pathway is clearly important in the regulation of FOXO signaling, another mechanism of regulation, acetylation, appears to be equally important in regulating FOXO signaling, at least in cultured non-muscle cell. However, it is currently unknown whether acetylation of FOXO factors is a regulatory mechanism of FOXO signaling in skeletal muscle during any condition of muscle atrophy. The overall objective of the current proposal is to determine the role of acetyltransferase (HAT) proteins and deacetylase (HDAC) proteins, and acetylation and deacetylation of FOXO factors, in regulating FOXO signaling as it relates to skeletal muscle atrophy. To address this, in Aim 1 we will transfect C2C12 skeletal muscle cells with wild type (WT) or dominant negative (d.n.) HAT proteins and determine their regulation of endogenous FOXO signaling. We will subsequently select one HAT protein for further study in whole skeletal muscle during muscle disuse and cancer.
In Aim 2 we will transfect C2C12 skeletal muscle cells with wild type (WT) or dominant negative (d.n.) HDAC proteins and determine their regulation of endogenous FOXO signaling. We will subsequently select one HDAC protein for further study in whole skeletal muscle during muscle disuse and cancer.
In Aim 3 we will transfect C2C12 skeletal muscle cells with plasmids encoding FOXO acetylation mutants that mimic either the acetylated or deacetylated forms of FOXO and determine their regulation of FOXO signaling. In each of these Aims we will measure FOXO transcriptional activity, FOXO- DNA binding, FOXO cellular localization, post-translational modifications of FOXO factors, the transcription of a sub-set of known FOXO target genes, and skeletal muscle fiber cross sectional area. The findings from these experiments will lead to a greater understanding of the regulation of FOXO signaling as it relates to skeletal muscle atrophy.
Skeletal muscle wasting is associated with a variety of conditions, including cast immobilization, bed rest, denervation, cancer, sepsis, diabetes and chronic heart failure. In the proposed work we will study a regulatory mechanism of a signaling pathway that is known to regulate skeletal muscle size, to gain a better understanding of how this pathway is controlled. A more comprehensive understanding of the regulation of this pathway is important for the identification of therapeutic targets for muscle wasting.
|Ahn, Bumsoo; Beharry, Adam W; Frye, Gregory S et al. (2015) NAD(P)H oxidase subunit p47phox is elevated, and p47phox knockout prevents diaphragm contractile dysfunction in heart failure. Am J Physiol Lung Cell Mol Physiol 309:L497-505|
|Beharry, Adam W; Judge, Andrew R (2015) Differential expression of HDAC and HAT genes in atrophying skeletal muscle. Muscle Nerve 52:1098-101|
|Ryder, Daniel J; Judge, Sarah M; Beharry, Adam W et al. (2015) Identification of the Acetylation and Ubiquitin-Modified Proteome during the Progression of Skeletal Muscle Atrophy. PLoS One 10:e0136247|
|Reid, Michael B; Judge, Andrew R; Bodine, Sue C (2014) Rebuttal from Michael B. Reid, Andrew R. Judge and Sue C. Bodine. J Physiol 592:5351|
|Judge, Sarah M; Wu, Chia-Ling; Beharry, Adam W et al. (2014) Genome-wide identification of FoxO-dependent gene networks in skeletal muscle during C26 cancer cachexia. BMC Cancer 14:997|
|Reid, Michael B; Judge, Andrew R; Bodine, Sue C (2014) CrossTalk opposing view: The dominant mechanism causing disuse muscle atrophy is proteolysis. J Physiol 592:5345-7|
|Beharry, Adam W; Sandesara, Pooja B; Roberts, Brandon M et al. (2014) HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy. J Cell Sci 127:1441-53|
|Roberts, Brandon M; Ahn, Bumsoo; Smuder, Ashley J et al. (2013) Diaphragm and ventilatory dysfunction during cancer cachexia. FASEB J 27:2600-10|
|Senf, Sarah M; Howard, Travis M; Ahn, Bumsoo et al. (2013) Loss of the inducible Hsp70 delays the inflammatory response to skeletal muscle injury and severely impairs muscle regeneration. PLoS One 8:e62687|
|Roberts, B M; Frye, G S; Ahn, B et al. (2013) Cancer cachexia decreases specific force and accelerates fatigue in limb muscle. Biochem Biophys Res Commun 435:488-92|
Showing the most recent 10 out of 13 publications