Effects of ursolic acid on sub-lesional muscle pathology in a contusion model of spinal cord injury

Abstract

Spinal Cord Injury (SCI) results in severe sub-lesional muscle atrophy and fiber type transformation from slow oxidative to fast glycolytic, both contributing to functional deficits and maladaptive metabolic profiles. Therapeutic countermeasures have had limited success and muscle-related pathology remains a clinical priority. mTOR signaling is known to play a critical role in skeletal muscle growth and metabolism, and signal integration of anabolic and catabolic pathways. Recent studies show that the natural compound ursolic acid (UA) enhances mTOR signaling intermediates, independently inhibiting atrophy and inducing hypertrophy. Here, we examine the effects of UA treatment on sub-lesional muscle mTOR signaling, catabolic genes, and functional deficits following severe SCI in mice. We observe that UA treatment significantly attenuates SCI induced decreases in activated forms of mTOR, and signaling intermediates PI3K, AKT, and S6K, and the upregulation of catabolic genes including FOXO1, MAFbx, MURF-1, and PSMD11. In addition, UA treatment improves SCI induced deficits in body and sub-lesional muscle mass, as well as functional outcomes related to muscle function, motor coordination, and strength. These findings provide evidence that UA treatment may be a potential therapeutic strategy to improve muscle-specific pathological consequences of SCI.

A 50 kdyne contusion spinal cord injury with or without the drug SS‐31 was not associated with major changes in muscle mass or gene expression 14 d after injury in young male mice

“…Additional likely factors for this loss are stress from the trauma itself alongside any related surgical procedure, reduced drinking despite ad libitum access even while paralyzed, disruption in thermoregulation as well as muscle disuse and possible hypermetabolism (Harris et al, 2019; Thibault‐Halman et al, 2011). Our model of moderate SCI is consistent with the pre‐clinical literature as we show sustained body mass loss compared to sham controls across 14 d (Bigford et al, 2018; Graham et al, 2020).…”

Cardiometabolic risks and atherosclerotic disease in ApoE knockout mice: Effect of spinal cord injury and Salsalate anti-inflammatory pharmacotherapy

“…A point of consideration is the initial decrease in activity due to injury. Although there is an established and well-defined locomotor recovery observed in our model of injury [ 42 , 46 ], the initial depression in activity level due to SCI may be a contributing factor to the disease pathology. Nonetheless, this fact does not change the conclusions reached in this study.…”

“…injection. Pharmacotherapy was given once daily for 1-month following SCI, consistent with recent evidence indicating efficacy in mice [ 42 , 43 ]. (*These treatment and injury control groups showed no behavioral , biological and/or statistical difference from untreated and uninjured groups , and therefore were removed from analysis) .…”

“…Surgeries were performed at the Animal and Surgical Core Facility of the Miami Project to Cure Paralysis As we previously described [ 42 , 44 , 45 ], contusion injury was induced with the Infinite Horizon Impactor device adapted to the mouse. The infinite Horizon impactor device has been established in producing precise, graded contusion, with reproducible lesion volume and functional outcomes assessed using Basso, Beattie, Bresnahan (BBB) and Basso Mouse Scale (BMS) [ 46 ] open-field locomotor rating scales [ 47 ].…”

Pathophysiology, Biomarkers, and Therapeutic Modalities Associated with Skeletal Muscle Loss Following Spinal Cord Injury

“…The use of steroids in the acute SCI setting has dramatically decreased in recent years as more recent data demonstrated the lack of efficacy [19,58]. However, ursolic acid, an anabolic compound, injected intraperitonially once per day, has been used to attenuate muscular atrophy and promote signaling pathways for protein synthesis [59]. Animal models show that the administration of ursolic acid decreases atrophy by >50% in the first seven days after injury [58].…”