@misc{10481/107739,
year = {2026},
url = {https://hdl.handle.net/10481/107739},
abstract = {Abstract
Background
Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are essential for cellular homeostasis and play a crucial role in lipid metabolism and calcium signaling. In skeletal muscle (SKM), MAMs contribute to metabolic flexibility, and their disruption is implicated in metabolic disorders such as diabesity (obesity and its associated type 2 diabetes). Melatonin, known for its antioxidant, circadian rhythm and metabolic regulatory effects, has been shown to preserve ER and mitochondrial function. This study explores whether melatonin could restore organellar membrane integrity and phospholipid composition in SKM, promoting MAM reassembly under diabesity conditions.
Methods
5-Weeks-old male and female Zücker diabetic fatty (ZDF) and lean (ZL) rats were subdivided into untreated control group (C) and treated with oral melatonin group (M, 10 mg/kg/day in drinking water for 12 weeks). MAM integrity and ER‒mitochondria interactions in the vastus lateralis (VL) muscle were assessed via both in situ proximity ligation assay (PLA) and transmission electron microscopy. Mitochondrial membrane integrity was evaluated by measuring mitochondrial permeability transition pore (mPTP) opening and cytochrome C release. Mitochondrial and ER phospholipid composition was analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). 
Results
In this study, we observed for the first time that melatonin promoted MAM assembly and ER‒mitochondria contacts in the VL from both sex obese diabetic rats. It also improved mitochondrial membrane integrity and reduced cytosolic cytochrome C release. In mitochondria, melatonin restored oxidized cardiolipin (CLox) to total cardiolipin (CL) ratio by decreasing CLox and increasing total CL and its species (CL (72:7), CL (76:12)). In the ER, melatonin restored the phosphatidylcholine (PC) to phosphatidylethanolamine (PE) ratio by reducing total PC, and specific PC species (PC (38:2) and PC (42:6)) while increasing total PE and specific PE species (PE (34:0), PE (36:2), PE (40:7), PE (40:8)). 
Conclusions
These findings highlight the potential role of melatonin as a therapeutic agent for preserving SKM mitochondrial membrane integrity and inter-organellar communication via MAM assembly during diabesity.  Furthermore, the restoration of ER‒mitochondrial contacts by melatonin contributes to the maintenance of proper phospholipid exchange between both organelles, restoring the ER membrane phospholipid composition, and mitigating the metabolic dysfunctions associated with diabesity.},
title = {Melatonin promotes skeletal muscle mitochondria-associated endoplasmic reticulum membrane contacts by restoring organellar membrane integrity and phospholipid composition in Zücker diabetic fatty rats of both sexes},
author = {Salagre, D and Villalón-Mir, M and Rieusset, J and Agil Abdalla, Mhmad Ahmad},
}