SUN-226 - Angiotensin 1-7 (Ang1-7) as a Potential Therapeutic Modulator of Skeletal Muscle Inflammation and Atrophy

Background: Skeletal muscle dysfunction is a central feature of metabolic syndrome (MetSyn) and aging, contributing to insulin resistance, chronic inflammation, and progressive loss of muscle mass and function. Experimental and clinical evidence indicates that dysregulation of the renin–angiotensin–aldosterone system, particularly chronic overactivation of the angiotensin II (Ang II) pathway, adversely affects skeletal muscle. Ang II promotes muscle atrophy, inflammation, oxidative stress, and fibrotic remodeling via impaired insulin signaling, activation of proteolytic pathways, and induction of profibrotic cytokines, leading to reduced regenerative capacity and sarcopenia in metabolic disease and aging.

Objective: To investigate the effects of Angiotensin 1-7 (Ang1-7) on skeletal muscle atrophy, inflammation, regeneration, and structural integrity in experimental models of MetSyn and aging.

Methods: MetSyn was induced in rats using a fructose-fed diet (n=5, 6 months), alongside an aged cohorts (n=5, 17 months). Ang1-7 was administered by continuous infusion using Alzet mini-pumps. Gastrocnemius muscle was analyzed by quantitative real-time PCR for genes related to muscle atrophy, regeneration, inflammation, and calcium-dependent contraction. Muscle morphology was assessed by myofiber cross-sectional area (CSA).

Results: Young fructose-fed MetSyn and aged rats exhibited increased expression of the atrophy-related E3 ubiquitin ligases Atrogin-1 (MAFbx) and MuRF1 and the profibrotic cytokine TGF-β, alongside altered expression of regeneration-related genes (MyoD, Myogenin) and genes involved in calcium-dependent contraction. Molecular features consistent with impaired leptin responsiveness suggested skeletal muscle leptin resistance. Ang1-7 significantly downregulated Atrogin-1, MuRF1, and TGF-β, restored MyoD and Myogenin expression, normalized calcium-handling gene expression, and reduced long-chain fatty acyl-CoA ligase 4 (ACSL4), indicating improved lipid handling. These changes were associated with increased myofiber CSA in aged animals.

Conclusion: Ang1-7 protects skeletal muscle by suppressing atrophy and inflammatory signaling while promoting regeneration and structural maintenance, supporting its potential as a potential therapeutic target in MetSyn and aging.