The Monocrotaline Model of Hypertension Leads to Cachexia in Male but Not Female Mice

The monocrotaline (MCT) model of cardiac cachexia is a pharmaceutical approach to pulmonary hypertension that has been used to study heart failure and muscle wasting in rodents; however, little is known of how this pyrrolizidine alkaloid leads to peripheral changes in organ function and body mass, and sex differences have not been adequately compared.

Ten- to 12-week-old male and female C57BL/6N mice were treated weekly with MCT (200 mg/kg) for 8 weeks. Body weight, feeding behaviour and stool output were monitored weekly. In the final week, endurance was measured via a treadmill fatigue study. Upon termination, organs were weighed and processed for histochemistry and downstream gene expression analysis.

Males were more susceptible to MCT-induced weight loss. No change in gross heart or skeletal muscle mass was observed in either sex, though lung mass was elevated in both sexes and cardiomyocyte size was larger in males (p < 0.05). MCT reduced the cross-sectional area of the tibialis anterior muscle in both sexes (p < 0.05), but this did not correspond to changes in endurance, as the treadmill fatigue study revealed no change in total time or distance run in response to MCT in either sex. RNA-seq analysis of the gastrocnemius muscle showed no significant changes in gene expression when compared within either the male or female cohort (n = 3), but when pooled (n = 6), MCT reduced gene pathways associated with mitochondrial function, adipogenesis and DNA repair and upregulated pathways associated with inflammation. Total fat mass was reduced by 40% in male mice in response to MCT, mainly because of significant reductions in inguinal white and brown interscapular adipose tissue mass. This was independent of food intake and intestinal distress, as no differences in stool wet:dry output or feeding behaviours were observed in either sex. Gene expression and immunohistochemical analysis of inguinal fat suggest that adipose tissue within males is particularly sensitive to MCT, as Tnfa, Ppargc1a and Zfp516 were upregulated, and there was a significant interaction between sex and MCT on Retn and Pnpl2a (aka Atgl) expression.

These data suggest sex-dependent physiological responses of mice to MCT, where adipose tissue loss is more pronounced in males as a result of adipose tissue inflammation and metabolic activation. In contrast, conserved atrophic effects of MCT are observed within skeletal muscle, irrespective of sex. Further research using this model should consider sex-dependent responses.