Physiology · May 2026
Altered mitochondrial bioenergetics in skeletal muscle of horses with pituitary pars intermedia dysfunction
By Clary BL, Ellis K, Kimura S et al.
Pituitary pars intermedia dysfunction (PPID) is an age-related endocrine disorder that affects approximately 20% of aged horses. Common clinical signs associated with PPID include hypertrichosis, lethargy, laminitis, sweating disorders, and a profound decrease in muscle mass. PPID is caused by neurodegeneration of dopaminergic neurons within the hypothalamus resulting in a loss of dopaminergic inhibition of the pituitary pars intermedia. Since this dopaminergic degeneration parallels the pathogenesis of Parkinson’s disease (PD) in human patients, PPID is often considered analogous to PD. PD is associated with mitochondrial dysfunction, particularly at complex I, and an increase in reactive oxygen species (ROS) production. While mitochondrial dysfunction is well known in PD, no studies have investigated mitochondrial dysfunction in PPID. Our objective was to diagnose mitochondrial bioenergetics in skeletal muscle of horses with PPID. We hypothesized that in PPID muscle, there would be less respiratory conductance, antioxidant buffering capacity (AoxBC), and mitochondrial enzyme kinetic activity when compared to the control groups. Skeletal muscle biopsies from horses with PPID along with healthy age-matched and young controls were used to investigate mitochondrial function (n=6/group). Respiratory conductance, the ability of mitochondria to match respiration to energetic demand, was assessed in permeabilized myofiber bundles using high-resolution respirometry (Oroboros). AoxBC, the balance between produced and emitted ROS, was assessed in permeabilized myofiber bundles using a fluorometric technique (Horiba). Enzyme kinetic assays were conducted for citrate synthase and complex I using muscle homogenate and spectrophotometry. Data were analyzed using a one-way ANOVA (JMP) with Tukey’s post-hoc analyses. Citrate synthase (CS) is a well-established marker for mitochondrial content in skeletal muscle. There was significantly less citrate synthase activity in PPID muscle when compared to both the young (48.0% decrease) and aged (40.9% decrease) controls (main effect, p=0.0166). This suggests that there is decreased mitochondrial content in muscle from PPID horses compared to the young and aged controls. Additionally, all functional data were normalized to CS to account for differences in mitochondrial content. Contrary to our hypothesis, complex I kinetic activity was greater in PPID muscle compared to both control groups (p=0.0033). AoxBC was greater in permeabilized myofibers from PPID horses compared to young (63.1% increase) and aged-matched healthy (48.1% increase) controls (main effect, p=0.0278). Respiratory conductance was not significantly different among PPID, young controls, and age-matched healthy controls (main effect, p=0.1440). While these data are unexpected, they are likely driven by the significant decrease in citrate synthase, indicating that while there are fewer mitochondria in PPID muscle samples, they are more bioenergetically efficient at various processes. These results suggest a compensatory upregulation of mitochondrial efficiency that should be further investigated. In conclusion, this data suggests PPID results in alterations in mitochondrial bioenergetics, which is potentially contributing to the generalized muscle loss and other dysfunction seen in horses with PPID. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.