Inhibiting myostatin reverses muscle fibrosis through apoptosis

Advance Online Publication June 8, 2012 doi: 10.1242/?jcs.090365 Zhao Bo Li, Jiangyang Zhang and Kathryn R. Wagner*?*Communicating Author: Kathryn R. Wagner, M.D., Ph.D., Center for Genetic Muscle Disorders, The Kennedy Krieger Institute, The Johns Hopkins School of Medicine, 707 North Broadway, Baltimore, MD 21205, 443-923-9525 (t), 443-923-9545 (f), wagnerk{at}kennedykrieger.orgSkeletal muscle fibrosis is a defining feature of the muscular dystrophies in which contractile myofibers are replaced by fibroblasts, adipocytes and extracellular matrix. This maladaptive response of muscle to repetitive injury is progressive, self-perpetuating and thus far, has been considered irreversible. We have previously shown that myostatin, a known endogenous modulator of muscle growth, stimulates normal muscle fibroblasts to proliferate. Here, we demonstrate that myostatin also regulates the proliferation of dystrophic muscle fibroblasts, and increases resistance of fibroblasts to apoptosis through Smad and MAPK signaling. Inhibiting myostatin signaling pathways with a soluble activin IIB receptor (ActRIIB.Fc), reduces resistance of muscle fibroblasts to apoptosis in vitro. Systemic administration of ActRIIB.Fc in senescent mdx mice, a model of muscular dystrophy, significantly increases the number of muscle fibroblasts undergoing apoptosis. This leads to the reversal of pre-existed muscle fibrosis as determined by histological, biochemical and radiographical criteria. These results demonstrate that skeletal muscle fibrosis can be pharmacologically reversed through induction of fibroblast apoptosis.

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Regulation of apoptosis by Bat3-enhanced YWK-II protein/APLP2 stability

Advance Online Publication May 28, 2012 doi: 10.1242/?jcs.086553 YWK-II protein/APLP2 is a member of an evolutionarily conserved protein family that includes amyloid precursor protein (APP) and amyloid precursor like protein-1 (APLP1). We have previously demonstrated that YWK-II/APLP2 functions as a novel G0-protein-coupled receptor for Müllerian inhibiting substance (MIS) in cell survival. However, factors regulating the stability and turnover of YWK-II/APLP2 have not been identified. Here we present evidence that human leukocyte antigen-B-associated transcript 3 (Bat3), an important regulator involved in apoptosis, can interact with YWK-II/APLP2 and enhance its stability by reducing its ubiquitination and degradation by the ubiquitin-proteasome system. Co-expression of different Bat3 domain deletion constructs with YWK-II/APLP2 reveals that the proline-rich domain of Bat3 is required for its binding to YWK-II/APLP2. In addition, we find that the protein levels of YWK-II/APLP2 could be enhanced by nuclear export of Bat3 under apoptotic stimulation. We also find elevated levels of Bat3 and YWK-II/APLP2 in human colorectal cancer with a positive correlation between the two. Taken together, these results have revealed a previously undefined mechanism regulating cell apoptosis and suggest that aberrant enhancement of YWK-II/APLP2 by nuclear export of Bat3 may play a role in cancer development by inhibiting cell apoptosis.

This work was supported by grants from the National program for the Important Research Plan (2011CB944302, 2012CB944902/903), National Key Technology Support Program (2012BAI31B08), State Key Laboratory Special Fund (2060204), 111 Project (B08007) from Ministry of Education and the Focused Investment Scheme of The Chinese University of Hong Kong.

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