Sirtuin 3 deficiency accelerates Angiotensin II-induced skeletal muscle atrophy

ABSTRACT

Background: It has been reported that Angiotensin II (Ang II) induced skeletal muscle atrophy. However, the precise mechanisms remain elusive. Sirtuin 3 (SIRT3), an NAD-dependent deacetylase, plays a central role in maintaining cellular metabolic homeostasis. This work aims to determine the role of SIRT3-mediated cellular metabolism in skeletal muscle wasting.

Methods and Results: Eight-week-old male wild-type (WT) and SIRT3 knockout (SIRT3 KO) mice were infused with Ang II or saline for 4 weeks. Ang II induces skeletal muscle atrophy by inducing expression of the muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) and atrogin-1, accompanied by a reduction in SIRT3 in skeletal muscle. SIRT3 deficiency accelerated Ang II-induced loss of lean mass and protein hyper-acetylation, while the activities of mitochondrial oxidative enzymes, such as complex I and complex V, were significantly decreased. Furthermore, SIRT3 deficiency accelerated the Ang II-induced shift from slow-twitch towards fast-twitch fibres. Similarly, the three major rate-limiting enzymes in the glycolytic pathway, hexokinase 2 (HK2), phosphofructokinase-1(PFK) and pyruvate kinase (PK), were upregulated in Ang II-treated SIRT3 KO mice.

Conclusion: These studies indicate that SIRT3 deficiency augmented Ang II-induced fibre-type shifting and metabolic reprogramming.

KEYWORDS:

• Atrophy
• SIRT3
• hypertension
• glycolysis

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary Data

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Additional information

Funding

This study was supported by grants from the National Natural Science Foundation of China [81472099] and Shanghai Science and Technology Committee [19DZ1200700].