Δ-15 desaturase prevents high-fat diet-induced skeletal muscle atrophy in mice

Obesity has become a worldwide public health concern and is tightly associated with multiple metabolic complications. A dietary imbalance characterized by an elevated n-6/n-3 polyunsaturated fatty acid (PUFAs) ratio provokes systemic inflammation and exacerbates obesity-linked skeletal muscle atrophy. However, it remains incompletely understood whether the elevation of endogenous n-3 PUFAs protects against skeletal muscle homeostasis disruption. An obese mouse model was created by feeding mice with a HFD to examine the potential beneficial impacts of endogenous n-3 PUFAs on skeletal muscle health. Transgenic (TG) mice engineered to express an active Δ15 fatty acid desaturase (Δ15Des), an enzyme responsible for converting n-6 PUFAs to n-3 PUFAs, were used as the experimental group, and wild-type (WT) C57BL/6 mice served as the control group. All mice were assigned to three dietary regimens, including a normal diet (ND), an HFD, and an HFD supplemented with arachidonic acid (HFDA). After 12 weeks of intervention, various assessments were carried out. Distinct pathological alterations were observed in the gastrocnemius muscle of WT mice under HFD treatment. TG mice presented elevated n-3 PUFA levels, reduced n-6 PUFA levels, significantly decreased body weight (BW), less adipose tissue mass and lowered ectopic fat accumulation, along with better-preserved gastrocnemius muscle structure. Further analyses showed that obesity-induced skeletal muscle atrophy was ameliorated in TG mice. Reduced inflammation, decreased endoplasmic reticulum (ER) stress and mitochondrial autophagy markers, downregulated expression of muscle atrophy factors and upregulated expression of myogenic regulatory factors were also detected in TG mice. The expression of Δ15-desaturase in TG mice facilitates the endogenous conversion of long-chain n-6 PUFAs to n-3 PUFAs. This effect attenuates inflammation and ER stress, improves mitochondrial function, and alleviates obesity-related skeletal muscle atrophy. The findings provide a theoretical foundation for clinical interventions targeting fatty acid (FA) metabolism.