Disruption of Rab9-dependent mitophagy contributes to menopause-induced sarcopenia.

Area of Science:

• * Gerontology
• * Cellular Biology
• * Mitochondrial Biology

Background:

• * Sarcopenia, a significant cause of frailty in postmenopausal women, is associated with mitochondrial dysfunction, but the precise mechanisms are not fully understood.
• * Mitophagy, a crucial mitochondrial quality control pathway, is implicated in cellular health and aging processes.

Purpose of the Study:

• * To investigate the role of mitophagy in postmenopausal sarcopenia.
• * To elucidate the underlying molecular mechanisms linking estrogen deficiency to sarcopenia.
• * To explore potential therapeutic interventions for sarcopenia by targeting mitophagy.

Main Methods:

• * Establishment of a postmenopausal mouse model via ovariectomy and assessment of nicotinamide mononucleotide (NMN) treatment.
• * In vitro studies using human skeletal muscle myoblasts (HSMMs) with estrogen (E2) deficiency or supplementation.
• * Modulation of Rab9 expression using CRISPR activation in HSMMs and analysis of mitophagy markers and mitochondrial function.

Main Results:

• * Ovariectomized mice and E2-deficient HSMMs showed reduced muscle mass, impaired differentiation, increased senescence, and compromised mitochondrial function.
• * Estrogen deficiency reduced mitophagy, specifically through a Rab9-dependent alternative autophagy pathway, evidenced by decreased Rab9 expression and lysosomal colocalization.
• * Overexpression of Rab9 in E2-deficient cells restored mitophagy, improved mitochondrial function, reduced senescence, and promoted skeletal muscle differentiation. NMN treatment in mice yielded similar benefits.

Conclusions:

• * Estrogen deficiency impairs Rab9-dependent mitophagy, contributing to mitochondrial dysfunction and sarcopenia in postmenopausal women.
• * Restoring Rab9-dependent mitophagy effectively improves mitochondrial quality control and muscle function.
• * Rab9-dependent mitophagy represents a promising therapeutic target for managing postmenopausal sarcopenia.