RESUMEN
Elevated plasma branched-chain amino acids (BCAAs) are strongly associated with obesity, insulin resistance (IR), and diabetes in humans and rodent models. However, the mechanisms of BCAA dysregulation and its systemic, organ, and cell-specific implications in the development of obesity and IR are not well understood. To gain mechanistic insight into the causes and effects of plasma BCAA elevations, we leveraged mouse models with high circulating BCAA levels prior to the onset of obesity and IR. Young mice lacking ankyrin-B in white adipose tissue (WAT) or bearing an ankyrin-B variant that causes age-driven metabolic syndrome exhibit downregulation of BCAA catabolism selectively in WAT and excess plasma BCAAs. Using cellular assays, we demonstrated that ankyrin-B promotes the surface localization of the amino acid transporter Asct2 in white adipocytes, and its deficit impairs BCAA uptake. Excess BCAA supplementation worsened glucose tolerance and insulin sensitivity across genotypes. In contrast, BCAA overconsumption only increased adiposity in control mice, implicating WAT utilization of BCAAs in their obesogenic effects. These results shed light into the mechanistic underpinnings of metabolic syndrome caused by ankyrin-B deficits and provide new evidence of the relevance of WAT in the regulation of systemic BCAA levels, adiposity, and glucose homeostasis.
RESUMEN
Osteogenesis imperfecta (OI) is a genetic connective tissue disorder characterized by compromised skeletal integrity, altered microarchitecture, and bone fragility. Current OI treatment strategies focus on bone antiresorptives and surgical intervention with limited effectiveness, and thus identifying alternative therapeutic options remains critical. Muscle is an important stimulus for bone formation. Myostatin, a TGF-ß superfamily myokine, acts through ActRIIB to negatively regulate muscle growth. Recent studies demonstrated the potential benefit of myostatin inhibition with the soluble ActRIIB fusion protein on skeletal properties, although various OI mouse models exhibited variable skeletal responses. The genetic and clinical heterogeneity associated with OI, the lack of specificity of the ActRIIB decoy molecule for myostatin alone, and adverse events in human clinical trials further the need to clarify myostatin's therapeutic potential and role in skeletal integrity. In this study, we determined musculoskeletal outcomes of genetic myostatin deficiency and postnatal pharmacological myostatin inhibition by a monoclonal anti-myostatin antibody (Regn647) in the G610C mouse, a model of mild-moderate type I/IV human OI. In the postnatal study, 5-week-old wild-type and +/G610C male and female littermates were treated with Regn647 or a control antibody for 11 weeks or for 7 weeks followed by a 4-week treatment holiday. Inhibition of myostatin, whether genetically or pharmacologically, increased muscle mass regardless of OI genotype, although to varying degrees. Genetic myostatin deficiency increased hindlimb muscle weights by 6.9% to 34.4%, whereas pharmacological inhibition increased them by 13.5% to 29.6%. Female +/mstn +/G610C (Dbl.Het) mice tended to have similar trabecular and cortical bone parameters as Wt showing reversal of +/G610C characteristics but with minimal effect of +/mstn occurring in male mice. Pharmacologic myostatin inhibition failed to improve skeletal bone properties of male or female +/G610C mice, although skeletal microarchitectural and biomechanical improvements were observed in male wild-type mice. Four-week treatment holiday did not alter skeletal outcomes. © 2020 American Society for Bone and Mineral Research (ASBMR).