# Irisin Increases Sirtuin 1 to Improve Glucocorticoid-Induced Sarcopenia and Mitochondrial Dysfunction

## TL;DR

Irisin helps reverse muscle loss caused by glucocorticoids by boosting SIRT1 activity and improving muscle function and mitochondrial health.

## Contribution

This study reveals that irisin alleviates glucocorticoid-induced sarcopenia through SIRT1 activation, offering a novel therapeutic approach.

## Key findings

- Irisin supplementation rescues muscle mass and function in sarcopenic mice.
- Irisin activates SIRT1, which suppresses proteasomal degradation and enhances protein synthesis.
- Irisin promotes mitochondrial biogenesis and restores contractile function in dystrophic fibers.

## Abstract

What are the main findings?
During the progression of glucocorticoid-induced metabolic sarcopenia, FNDC5/irisin levels are reduced, whereas supplementation of FNDC5/irisin alleviates glucocorticoid-induced metabolic sarcopenia.

During the progression of glucocorticoid-induced metabolic sarcopenia, FNDC5/irisin levels are reduced, whereas supplementation of FNDC5/irisin alleviates glucocorticoid-induced metabolic sarcopenia.

What is the implication of the main finding?
FNDC5/irisin ameliorates glucocorticoid-induced muscle protein metabolic imbalance via activation of sirtuin 1, thereby restoring muscle protein homeostasis.

FNDC5/irisin ameliorates glucocorticoid-induced muscle protein metabolic imbalance via activation of sirtuin 1, thereby restoring muscle protein homeostasis.

Sarcopenia, characterized by progressive skeletal muscle mass, strength, and functional loss, imposes a substantial global health burden. Irisin, a myokine derived from fibronectin type III domain-containing protein 5 (FNDC5), is critical for muscle health. Here, we investigate its role in mitigating glucocorticoid-induced sarcopenia using a mouse and C2C12 myotubes model. We quantified FNDC5/irisin levels in skeletal muscle and plasma and assessed muscle function (body weight, grip strength, wire-hanging, and locomotor activity), histology, and mitochondrial features following irisin administration to dexamethasone-treated mice. Western blot analyzed synthesis/hydrolysis regulators, apoptosis markers, and mitochondrial regulators in mouse muscle tissues and C2C12 myotubes. The results show that FNDC5/irisin was significantly downregulated in sarcopenic mice and atrophic C2C12 myotubes; exogenous irisin rescued muscle mass loss and functional impairment, improving body weight, muscle mass, grip strength, and mobility. Mechanistically, irisin bound SIRT1 with −12.7 kcal/mol affinity, activating a deacetylation cascade that suppressed FoxO3a transcriptional activity (attenuating proteasomal degradation) and enhanced mTORC1-mediated protein synthesis in C2C12 myotubes. Additionally, irisin potentiated PGC-1α signaling in mouse myocytes, promoting mitochondrial biogenesis and restoring contractile function in dystrophic fibers. Collectively, these findings demonstrate irisin alleviates glucocorticoid-induced muscle atrophy via SIRT1-dependent pathways, rebalancing muscle physiology and systemic energy homeostasis. This highlights irisin-based therapeutics as a promising exercise surrogate for sarcopenia management, offering novel clinical avenues.