Biology subjects

Meyer, G. A.

Publications and source records attributed to Meyer, G. A..

3 recordsLinked to original sources

bioRxiv2022

Site-1 Protease inhibits mitochondrial metabolism by controlling the TGF-β target gene MSS51

The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-{beta}1 target gene MSS51, which is an inhibitor of skeletal muscle mitochondrial metabolism. Despite the potential importance of MSS51 in the pathophysiology of obesity and musculoskeletal disease, how MSS51 is regulated is not entirely understood. Site-1 Protease (S1P) is a Golgi-resident protease that is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle and mitochondrial function are unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial metabolism. Disruption of S1P in mouse skeletal muscle and cultured myofibers leads to a reduction in MSS51 expression, increased muscle mass, and increased mitochondrial oxygen consumption. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing MSS51, suggesting that S1P inhibits mitochondrial metabolism by regulating the expression of MSS51. Furthermore, S1P suppression enhances TGF-{beta} signaling via the AKT pathway, potentially explaining muscle hypertrophy in S1P deficient mice. The discovery of S1P as a regulator of mitochondrial metabolism and muscle mass expands our understanding of TGF-{beta} signaling and suggests this protease could be a target for therapeutic intervention in muscle.

molecular biology↗

bioRxiv2022

Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB

The nuclear factor-{kappa}B (NF{kappa}B) pathway is a major thoroughfare for skeletal muscle atrophy and is driven by diverse stimuli. Targeted inhibition of NF{kappa}B through its canonical mediator IKK{beta} effectively mitigates loss of muscle mass across many conditions, from denervation to unloading to cancer. In this study, we used gain- and loss-of-function mouse models to examine the role of NF{kappa}B in muscle atrophy following rotator cuff tenotomy - a model of chronic rotator cuff tear. IKK{beta} was knocked down or constitutively activated in muscle-specific inducible transgenic mice to elicit a 2-fold gain or loss of NF{kappa}B signaling. Surprisingly, neither knockdown of IKK{beta} nor overexpression of caIKK{beta} significantly altered the loss of muscle mass following tenotomy. This finding was consistent across measures of architectural adaptation (fiber cross-sectional area, fiber length, fiber number), tissue pathology (fibrosis and fatty infiltration) and intracellular signaling (ubiquitin-proteasome, autophagy). Intriguingly, late-stage tenotomy-induced atrophy was exacerbated in male mice compared to female mice. This sex specificity was driven by ongoing decreases in fiber cross-sectional area, which paralleled the accumulation of large autophagic vesicles in male, but not female muscle. These findings suggest that tenotomy-induced atrophy is not dependent on NF{kappa}B and instead may be regulated by autophagy in a sex-specific manner.

physiology↗

bioRxiv2020

Adipose Tissue is a Critical Regulator of Osteoarthritis

Osteoarthritis (OA), the leading cause of pain and disability worldwide, disproportionally affects obese individuals. The mechanisms by which adipose tissue leads to the onset and progression of OA are unclear due to the complex interactions between the metabolic, biomechanical, and inflammatory factors that accompany obesity. We used a murine model of lipodystrophy (LD) to examine the direct contribution of adipose tissue to OA. Knee joints of LD mice were protected from spontaneous or post-traumatic OA, on either a chow and high fat diet, despite similar body weight and the presence of systemic inflammation. These findings indicate that adipose tissue itself plays a critical role in the pathophysiology of OA. Susceptibility to post-traumatic OA was reintroduced into LD mice using implantation of adipose tissue derived from wildtype animals or mouse embryonic fibroblasts that undergo spontaneous adipogenesis, implicating paracrine signaling from fat, rather than body weight, as a critical mediator of joint degeneration.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗