Impact of long-term rapamycin treatment on age-related osteoarthritis in common marmoset.

Objective: Pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) can attenuate experimental osteoarthritis (OA) in young, male preclinical models. However, the potential of mTOR inhibition as a therapeutic mechanism for OA remains unknown. The goal of this study was to determine if mTOR-inhibition by oral rapamycin can modify OA pathology in the common marmoset, a translational model of age-associated OA. Methods: microCT and histopathologic assessments of the knee were performed on formalin-fixed hindlimbs obtained from common marmosets treated with oral rapamycin (n=24; 1mg/kg/day) or parallel control group (n=41). Rapamycin started at 9.2±3.0 years old and lasted until death (2.1±1.5 years). In a subset of marmosets, contralateral hind limbs were collected to determine mTOR signaling in several joint tissues. Results: Rapamycin decreased P-RPS6Ser235/36 and increased P-Akt2Ser473 in cartilage, meniscus, and infrapatellar fat pad, suggesting inhibition of mTORC1 but not mTORC2 signaling. Rapamycin-treated marmosets had lower lateral synovium score versus control but there was no difference in the age-related increase in microCT or cartilage OA scores. Subchondral bone thickness and thickness variability were not different with age but were lower in rapamycin-treated geriatric marmosets, which was largely driven by females. Rapamycin also tended to worsen age-related meniscus calcification in female marmosets. Conclusion: Oral rapamycin attenuated mTORC1 signaling and may have caused feedback activation of mTORC2 signaling in joint tissues. Despite modifying site-specific aspects of synovitis, rapamycin did not modify the age-associated increase in OA in geriatric marmosets. Conversely, rapamycin may have had deleterious effects on meniscus calcification and lateral tibia subchondral bone, primarily in geriatric female marmosets.

The common marmoset as a translational model of age-related osteoarthritis.

Age-related osteoarthritis (OA) is a degenerative joint disease characterized by pathological changes in nearly every intra- and peri-articular tissue that contributes to disability in older adults. Studying the etiology of age-related OA in humans is difficult due to an unpredictable onset and insidious nature. A barrier in developing OA modifying therapies is the lack of translational models that replicate human joint anatomy and age-related OA progression. The purpose of this study was to determine whether the common marmoset is a faithful model of human age-related knee OA. Semi-quantitative microCT scoring revealed greater radiographic OA in geriatric versus adult marmosets, and the age-related increase in OA prevalence was similar between marmosets and humans. Quantitative assessments indicate greater medial tibial cortical and trabecular bone thickness and heterogeneity in geriatric versus adult marmosets which is consistent with an age-related increase in focal subchondral bone sclerosis. Additionally, marmosets displayed an age-associated increase in synovitis and calcification of the meniscus and patella. Histological OA pathology in the medial tibial plateau was greater in geriatric versus adult marmosets driven by articular cartilage damage, proteoglycan loss, and altered chondrocyte cellularity. The age-associated increase in medial tibial cartilage OA pathology and meniscal calcification was greater in female versus male geriatric marmosets. Overall, marmosets largely replicate human OA as evident by similar 1) cartilage and skeletal morphology, 2) age-related progression in OA pathology, and 3) sex differences in OA pathology with increasing age. Collectively, these data suggest that the common marmoset is a highly translatable model of the naturally occurring, age-related OA seen in humans.

Cardiorespiratory Responses to an Acute Bout of High Intensity Interval Training and Moderate Intensity Continuous Training on a Recumbent Handcycle in People With Spinal Cord Injury: A Within-Subject Design.

Objectives: To compare acute cardiorespiratory responses during high intensity interval training (HIIT) and moderate intensity continuous training (MICT) on a recumbent handcycle in persons with spinal cord injury (PwSCI). Methods: Eleven males and nine females with chronic SCI (T3 - L5), aged 23 (9) years, participated in this within-subject design. Based off peak power outputs from an incremental test to exhaustion, participants engaged in a HIIT and MICT session at matched workloads on a recumbent handcycle. Workloads (Joules), time, oxygen uptake (VO2), metabolic equivalent of task (MET), heart rate (HR), and energy expenditure (kcal) were recorded during HIIT and MICT. Results: Total workload was similar across HIIT (87820 ± 24021 Joules) and MICT sessions (89044 ± 23696 Joules; p > .05). HIIT (20.00 [.03] minutes) was shorter in duration than MICT (23.20 [2.56]; p < .01). Average VO2 (20.96 ± 4.84 vs. 129.38 ± 19.13 mL/kg/min O2), MET (7.54 ± 2.00 vs. 6.21 ± 1.25), and HR (146.26 ± 13.80 vs. 129.38 ± 19.13 beats per minute) responses were significantly greater during HIIT than MICT (p < .01). Participants burned significantly more kilocalories during HIIT (128.08 ± 35.65) than MICT (118.93 ± 29.58; p < .01) and at a faster rate (6.40 ± 1.78 [HIIT] vs. 5.09 ± 1.14 [MICT] kcal/min; p < .01). Conclusion: HIIT elicits greater increases in oxygen uptake and HR than MICT in PwSCI. In significantly less time, HIIT also burned more calories than MICT.

Moving forward: A review of continuous kinetics and kinematics during handcycling propulsion.

Wheelchair users (WCUs) face high rates of shoulder overuse injuries. As exercise is recommended to reduce cardiovascular disease prevalent among WCUs, it is becoming increasingly important to understand the mechanisms behind shoulder soft-tissue injury in WCUs. Understanding the kinetics and kinematics during upper-limb propulsion is the first step toward evaluating soft-tissue injury risk in WCUs. This paper examines continuous kinetic and kinematic data available in the literature. Attach-unit and recumbent handcycling are examined and compared. Athletic modes of propulsion such as recumbent handcycling are important considering the higher contact forces, speed, and power outputs experienced during these activities that could put users at increased risk of injury. Understanding the underlying kinetics and kinematics during various propulsion modes can lend insight into shoulder loading, and therefore injury risk, during these activities and inform future exercise guidelines for WCUs.

Propulsion kinetics of recumbent handcycling during high and moderate intensity exercise.

People with spinal cord injuries (PwSCI) are at high risk of developing cardiovascular disease (CVD). While regular exercise can reduce risk of CVD, PwSCI face various barriers to exercise, including high rates of upper limb injuries, especially in the shoulder. Handcycling high intensity interval training (HIIT), which consists of periods of high intensity exercise followed by rest, is a potential exercise solution, but the musculoskeletal safety of HIIT is still unknown. In this study, we characterized three-dimensional continuous applied forces at the handle during handcycling HIIT and moderate intensity continuous training (MICT). These applied forces can give an early indication of joint loading, and therefore injury risk, at the shoulder. In all three directions (tangential, radial, and lateral), the maximum applied forces during HIIT were larger than those in MICT at all timepoints, which may indicate higher contact forces and loads on the shoulder during HIIT compared to MICT. The tangential and radial forces peaked twice in a propulsion cycle, while the lateral forces peaked once. Throughout the exercises, the location of tangential peak 2 and radial peak 1 was later in HIIT compared to MICT. This difference in maximum force location could indicate either altered kinematics or muscular fatigue at the end of the exercise protocol. These changes in kinematics should be more closely examined using motion capture or other modeling techniques. If we combine this kinetic data with kinematic data during propulsion, we can create musculoskeletal models that more accurately predict contact forces and injury risk during handcycling HIIT in PwSCI.