| Abstract |
Right heart failure (RHF) is a common and deadly disease in aged populations. Extra-cardiac outcomes of RHF such as skeletal muscle atrophy contribute to morbidity and mortality. Despite the significance of maintaining right ventricular (RV) and muscle function, the mechanisms of RHF and muscle atrophy are unclear. Metformin (MET) improves cardiac and muscle function through the regulation of metabolism and the cellular stress response. However, whether MET is a viable therapeutic for RHF and muscle atrophy is not yet known. We used deuterium oxide labeling to measure individual protein turnover in the RV as well as subcellular skeletal muscle proteostasis in aged male mice subjected to 4 weeks of hypobaric hypoxia (HH)-induced RHF. Mice exposed to HH had elevated RV mass and impaired RV systolic function, neither of which was prevented by MET. HH resulted in a higher content of glycolytic, cardiac, and antioxidant proteins in the RV, most of which were inhibited by MET. The synthesis of these key RV proteins was generally unchanged by MET, suggesting MET accelerated protein breakdown. HH resulted in a loss of skeletal muscle mass due to inhibited protein synthesis alongside myofibrillar protein breakdown. MET did not impact HH-induced muscle protein turnover and did not prevent muscle wasting. Together, we show tissue-dependent responses to HH-induced RHF where the RV undergoes hypertrophic remodeling with higher expression of metabolic and stress response proteins. Skeletal muscle undergoes loss of protein mass and atrophy, primarily due to myofibrillar protein breakdown. MET did not prevent HH-induced RV dysfunction or muscle wasting, suggesting that the identification of other therapies to attenuate RHF and concomitant muscle atrophy is warranted. |
| Authors |
Danielle R. Bruns   , Benjamin D. McNair , Frederick F. Peelor , Agnieszka Borowik , Atul Pranay , Aykhan Yusifov , Benjamin F. Miller
|
| Journal Info |
Springer International Publishing | GeroScience , vol: 45
, iss: 4
, pages: 2545 - 2557
|
| Publication Date |
4/29/2023 |
| ISSN |
2509-2723 |
Type |
article |
| Open Access |
closed
|
| DOI |
https://doi.org/10.1007/s11357-023-00777-7 |
| Keywords |
Skeletal Muscle Atrophy (Score: 0.583915) , Metabolism (Score: 0.522582) , Metabolic Regulation (Score: 0.506343) , Muscle Regeneration (Score: 0.502247)
|
