Pathophysiology of sarcopenia in chronic pancreatitis: Insights from muscle biopsy and molecular profiling.

BACKGROUND AND AIM: Sarcopenia is a significant complication of chronic pancreatitis (CP), contributing to increased morbidity and adverse outcomes. Chronic inflammation and metabolic dysregulation may promote skeletal muscle wasting through catabolic signaling activation, though underlying molecular mechanisms remain incompletely understood. This study investigated molecular pathways associated with sarcopenia in CP.

METHODS

260 CP patients were evaluated for sarcopenia using skeletal muscle index (SMI) at L3 via CT, applying Asian ethnicity-specific cut-offs (<36.5 cm2/m2 men, <30.2 cm2/m2 women). Serum inflammatory and metabolic mediators were quantified by Luminex/ELISA assay. Rectus abdominis biopsies from sarcopenic (n = 10), non-sarcopenic (n = 7), and healthy controls (n = 6) underwent qPCR, Western blotting, immunohistochemistry, and electron microscopy.

RESULTS

Of 260 patients (median illness duration 36 months), 88 (33.8%) were sarcopenic (mean age 36.2 ± 10.6 years), with idiopathic CP the leading etiology (58.5%). Sarcopenic patients had significantly lower BMI (18.73 ± 2.90 vs. 21.93 ± 3.59 kg/m2, p < 0.001), elevated myostatin, activin A, and TIMP, and reduced IGF-1 (p < 0.05). Histology showed reduced myofiber cross-sectional area and increased fat infiltration; ultrastructural analysis revealed mitochondrial abnormalities with disrupted cristae and lipid accumulation. Sarcopenic muscle showed downregulated IGF-1/AKT/mTOR signaling (reduced AKT2, mTOR expression and phosphorylation of AKT, mTOR, p70S6K), activated myostatin/activin-SMAD2/3 signaling, upregulated FOXO3, increased MuRF1/MAFbx, and downregulated autophagy markers (LC3B, Beclin-1).

CONCLUSION

Sarcopenia is common in patients of chronic pancreatitis, and it is characterized by activation of catabolic signaling, impaired anabolic pathways, mitochondrial dysfunction, and defective autophagy. These findings are hypothesis-generating and, if confirmed in larger mechanistic studies, may help identify targets to mitigate muscle loss and improve outcomes.