Journal Article

Age-related adiponectin resistance in human skeletal muscle dysfunction: in vivo and in vitro evidence

Paolisso, Giuseppe, Capuano, Annalisa, Pesapane, Ada, Vietri, Maria Teresa, Zia, Asad, Tortorella, Giovanni, Barbieri, Michelangela, Scisciola, Lucia, Balzano, Nunzia, Fontanella, Rosaria Anna, Palazzo, Alberta Maria Maddalena, Basilicata, Manuela Giovanna, Joshi, Rashmi, Surina, Surina, Ulfat, Zeeshan, Arshad, Maryam

2026

Overview

Background Sarcopenia is an age-related condition characterized by the progressive decline of skeletal muscle mass and function. Although adiponectin is known for its anti-inflammatory and insulin-sensitizing effects that support muscle regeneration, paradoxically, elevated levels in older adults are linked to decreased muscle mass, strength, and performance. This study aimed to investigate the relationship between adiponectin levels, age, body composition, and functional status in elderly individuals, as well as to perform in vitro analyses of adiponectin resistance. Methods A cohort of 393 elderly subjects underwent anthropometric, bioimpedance, and functional assessments. Plasma adiponectin levels were measured by ELISA, and AdipoR1/AdipoR2 expression in peripheral blood mononuclear cells (PBMCs) was evaluated. In vitro, human skeletal muscle cells (SkMCs) were exposed to high concentrations (50 µM) of AdipoRon, a dual AdipoR1/AdipoR2 agonist, for 24 and 72 h. Analyses include cell viability, oxidative stress, protein homeostasis, autophagy, proteasome activity, and lipid metabolism. Results In elderly subjects, plasma adiponectin levels negatively correlated with BMI ( r =  -0.129; p  = 0.03), lean mass ( r =  -0.252; p  = 0.001), muscle mass ( r =  -0.296; p  = 0.001), and physical performance (SPPB score; r =  -0.163; p  = 0.007). After adjusting for BMI and fat mass, adiponectin levels positively correlated with age ( r  = 0.281; p  = 0.001). AdipoR2 expression in peripheral blood mononuclear cells was inversely associated with both age and adiponectin levels, suggesting adiponectin resistance in aging. In vitro, high dose of AdipoR agonist -AdipoRon exposure leads to oxidative stress, impaired proteostasis, dysregulated lipid metabolism, AdipoR2 receptor downregulation, and reduced cell viability. Together, these findings support a model in which elevated adiponectin in aging reflects adiponectin resistance and cellular stress rather than beneficial adiponectin signaling, contributing to muscle dysfunction. Conclusions These findings highlight a shift in adiponectin signaling during aging, with the downregulation of AdipoR2 promoting systemic adiponectin resistance. Excessive AMPK activity, in the context of impaired AdipoR2 function, contributes to redox imbalance and metabolic dysfunction in the skeletal muscle, favoring a “senescent-like” phenotype. Graphical Abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adiponectin / Adiponectin - blood / Adiponectin - metabolism / Adiponectin resistance / AdipoRon / Age / Aged / Aged, 80 and over / Aging / Aging - pathology / Agonists / Analysis / Autophagy / Autophagy - drug effects / Biological markers / Biomedical and Life Sciences / Biomedicine / Body Composition / Body fat / Cell Survival - drug effects / Cell viability / Cells / Cellular senescence / Cellular stress response / Diabetes / Down-regulation / Enzyme-linked immunosorbent assay / Female / Geriatrics / Homeostasis / Humans / Inflammation / Leukocytes (mononuclear) / Leukocytes, Mononuclear - metabolism / Lipid metabolism / Lipid Metabolism - drug effects / Male / Medical examination / Medicine/Public Health / Metabolism / Muscle, Skeletal - metabolism / Muscle, Skeletal - pathology / Muscle, Skeletal - physiopathology / Muscles / Musculoskeletal system / Older people / Oxidative stress / Oxidative Stress - drug effects / Peripheral blood mononuclear cells / Phenotypes / Piperidines - pharmacology / Prevention / Proteasome Endopeptidase Complex - metabolism / Proteasomes / Proteins / Receptors, Adiponectin - metabolism / Risk factors / Sarcopenia / Skeletal muscle / Skeletal muscle dysfunction / Software / Translational Signaling and System Biology