Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle mass

Abstract

The transforming growth factor-β (TGF-β) signaling network is a critical regulator of skeletal muscle mass and function and, thus, is an attractive therapeutic target for combating muscle disease, but the underlying mechanisms of action remain undetermined. We report that follistatin-based interventions (which modulate TGF-β network activity) can promote muscle hypertrophy that ameliorates aging-associated muscle wasting. However, the muscles of old sarcopenic mice demonstrate reduced response to follistatin compared with healthy young-adult musculature. Quantitative proteomic and transcriptomic analyses of young-adult muscles identified a transcription/translation signature elicited by follistatin exposure, which included repression of ankyrin repeat and SOCS box protein 2 (Asb2). Increasing expression of ASB2 reduced muscle mass, thereby demonstrating that Asb2 is a TGF-β network–responsive negative regulator of muscle mass. In contrast to young-adult muscles, sarcopenic muscles do not exhibit reduced ASB2 abundance with follistatin exposure. Moreover, preventing repression of ASB2 in young-adult muscles diminished follistatin-induced muscle hypertrophy. These findings provide insight into the program of transcription and translation events governing follistatin-mediated adaptation of skeletal muscle attributes and identify Asb2 as a regulator of muscle mass implicated in the potential mechanistic dysfunction between follistatin-mediated muscle growth in young and old muscles.

ASB1 differential methylation in ischaemic cardiomyopathy: relationship with left ventricular performance in end‐stage heart failure patients

“…ASB1 differential methylation in ischaemic cardiomyopathy been implicated as a negative regulator of skeletal muscle mass through the transforming growth factor beta pathway, indicating that increased levels prevents hypertrophy. 19 The limited data available in the literature on the specific function of ASB1, together with our results, suggest that this gene could be involved in the pathology of cardiac function. As demonstrated, gain of methylation of ASB1 CpG island closely relates to LV function, dimensions, and output, and none of the other 18 ASB family genes show such change, indicating that an increased degree of methylation may be an indicator of deteriorating haemodynamic and cardiac function.…”

“…Scant data are available about the specific function of ASB1 , relating it with alterations in spermatogenesis; moreover, no studies have been conducted in cardiac tissues, but its protein superfamily has relevant implications in controlling the skeletal muscle contractile apparatus structural fixation and adequate regulation of differentiation steps . ASB2 has been implicated as a negative regulator of skeletal muscle mass through the transforming growth factor beta pathway, indicating that increased levels prevents hypertrophy . The limited data available in the literature on the specific function of ASB1 , together with our results, suggest that this gene could be involved in the pathology of cardiac function.…”

“…[16][17][18] Moreover, members of this family have been related to skeletal muscle mass regulation. 19 Taking into account these previous data and the increasing evidence of the influence of epigenetic changes in the pathophysiology of human diseases, we hypothesize that the epigenetic changes in the ASB gene family may relate to the ischaemic left ventricular (LV) performance. We analysed specific gene methylation changes in patients with end-stage ischaemic cardiomyopathy (ICM) compared with those in control (CNT) subjects.…”

“…Interestingly, the gene family ASB codifies ankyrin repeat and SOCS box proteins that mediate, through their specific domains, protein–protein interactions, protein synthesis, and myogenesis and proteasomal degradation processes . Moreover, members of this family have been related to skeletal muscle mass regulation …”

Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease

“…Even using more stringent cutoff criteria (adjusted P value <0.05, ±twofold), 1,290 genes were significantly regulated. To better delineate genes that contribute to the synergistic response, our dataset was compared with gene changes reported previously in response to follistatin (26), which, Myostatin and activins synergize to regulate muscle mass. The right tibialis anterior (TA) muscles of 6-to 8-wk-old male C57BL/6 mice were injected with AAVs encoding for modified activin A prodomain, activin B prodomain, and/or myostatin prodomain (left TA muscles were injected with equivalent doses of an AAV lacking a transgene).…”