MOTS-c activates metabolism but paradoxically blunts reparative function in obese human mesenchymal stromal cells

Mesenchymal stromal cells (MSCs) hold significant therapeutic promise, largely dependent on robust mitochondrial function for their reparative capabilities. However, obesity severely compromises MSC metabolism and their ability to repair tissues. While MOTS-c, a mitochondria-derived peptide, is known to regulate cellular metabolism, its specific role in human MSC biology, particularly in the context of obesity-induced dysfunction, has remained unclear. This study aimed to investigate if restoring MOTS-c signaling could rescue the impaired functionality of adipose-derived MSCs from individuals with obesity.

MSCs were isolated from abdominal fat of n=6 patients with obesity (BMI ≥ 30 kg/m2) and n=6 lean donors (BMI < 30 kg/m2). These cells were then assessed in vitro for changes in proliferation, senescence (via p16 and p21 gene expression), TNF-α levels, and antioxidant gene expression following co-incubation with MOTS-c. For in vivo validation, the effects of MOTS-c pre-treatment on the reparative capacity of obese MSCs were evaluated in a murine model of renal artery stenosis, with renal perfusion, fibrosis, and tubular injury as primary endpoints.

Basal MOTS-c expression was significantly lower in MSCs derived from obese individuals compared to lean donors. Despite this, exogenous MOTS-c successfully restored intracellular MOTS-c levels and robustly activated AMPK signaling in the obese MSCs. However, this metabolic activation led to paradoxical outcomes: MOTS-c reduced MSC proliferation, increased the expression of senescence-associated genes (p16, p21), and upregulated TNF-α levels. In the in vivo murine model of renal artery stenosis, MOTS-c-pretreated obese MSCs failed to improve renal perfusion, fibrosis, or tubular injury. Furthermore, pretreatment with MOTS-c also blunted the reparative efficacy of MSCs derived from lean donors. > These findings reveal a critical dissociation between metabolic activation and functional stemness, suggesting that restoring mitochondrial metabolic signaling via MOTS-c is insufficient to reverse obesity-induced MSC dysfunction and may even exacerbate senescence and inflammation.