American Journal of Physiology - Lung Cellular and Molecular Physiology · 13 authors, 8 centres
This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.
In a mouse model of LPS-induced acute exacerbation of COPD, global deletion of the enzyme 11β-HSD1 unexpectedly increased muscle atrophy rather than protecting against it. The exacerbation was driven by elevated circulating corticosterone and enhanced glucocorticoid receptor signaling in muscle, rather than by increased local muscle inflammation.
This preclinical study used a transgenic mouse model with global deletion of 11β-HSD1 to investigate the enzyme's role in skeletal muscle atrophy during acute exacerbation of COPD, induced by intratracheal LPS administration. Contrary to the authors' hypothesis, 11β-HSD1 knockout mice exhibited increased muscle atrophy compared to wild-type controls. This was characterized by enhanced Ubiquitin 26S-proteasome-mediated degradation, suppressed anabolic signaling through the IGF-1/Akt/mTOR pathway (evidenced by lower phosphorylation of Akt, S6, 4E-BP1, and ULK1), and attenuated postnatal myonuclear accretion in vitro. Circulating corticosterone was significantly elevated in knockout animals, accompanied by increased glucocorticoid receptor signaling in muscle, including upregulation of the response gene Gilz. Notably, local muscle inflammatory signaling (NF-κB) and systemic IL-6 levels did not differ between genotypes, indicating the difference in atrophy was driven by glucocorticoid rather than inflammatory mechanisms. The authors propose that loss of 11β-HSD1 in the hypothalamus impaired negative feedback on the HPA axis, elevating circulating glucocorticoids. Limitations include the use of LPS rather than viral or mixed infectious triggers, and absence of direct protein synthesis measurements.
