Agility Project Awardees

Many different populations of cells have been purported to improve or impair musculoskeletal regeneration and repair. Dr. Baar has developed an in vitro human tendon/ligament organoid that can be used to determine the effect of exercise, nutrition, and hormones/cytokines on the structural and mechanical properties of these complex tissues. This project uses this model to:

• Study the effect of different immune cell types on tendon and ligament physiology and function
• Identify the optimal cell type(s) for promoting the functional improvement of the organoids
• Translate the results into a pre-clinical tendon injury model
• Determine the effect of orthobiologic delivery on the functional regeneration of the tendon

Watch Dr. Baar discuss the spatial aspects of tendon development and repair.

Currently there remain limited treatment methods to accelerate muscle regeneration and reduce fibrosis. Developing treatments through experimentation alone is challenging because of the dynamic interactions between many cell types, micro-environmental factors, and systemic factors, most notably sex hormones.

Estrogen levels are known to influence the muscle injury susceptibility and the timing of recovery from injury. This project’s goal is to develop an estrogen-specific muscle regeneration agent-based model (ABM). Specifically, Dr. Blemker and her team will:

1. Conduct coupled in vivo and in silico experiments to develop and validate the muscle regeneration ABM to account for the role of estrogen in regeneration
2. Use the ABM to determine the optimal combinations of growth factor interventions for muscle regeneration across a range of estrogen levels

A remarkable feature of skeletal muscle is its ability to adapt to different functional demands. Resistance training produces different changes compared with endurance training. Eccentric muscle contractions induce muscle damage in contrast to concentric contractions. The molecular underpinnings of these differences are unclear, yet they hold great potential to optimize performance and reduce injury.

This project has two goals:

• Modulate the strength and duration parameters of contractions to pursue the molecular pathways underlying strength or endurance exercise adaptations
• Employ defined models of eccentric vs. isometric or concentric contractions to identify specific changes in regional sites of injury and the inflammatory cell response associated with contraction-induced muscle damage

This project explores the use of a novel, point-of-care, non-invasive ultrasound device to evaluate athletic injuries. This ultrasound device, which is FDA-approved for imaging breast and liver diseases, has been repurposed to provide high-resolution 2D imaging of muscle compartment constituents and simultaneously measures tissue physiology: stiffness (elastic modulus) and strength as well as high-resolution imaging of microvascular blood flow at the level of 100 – 200μm vessels.

The Griffith University team is developing a suite of software and tools called The Digital Athlete-Australia (TDA-Aus) to advance our ability to create computational representations of the musculoskeletal system and athletic performance. Working in collaboration with the Alliance’s Digital Athlete moonshot, this project has three specific goals:

• Build a high-fidelity database architecture for TDA-Aus
• Formalize a TDA-Aus workflow that combines open-source software: OpenSim for musculoskeletal simulations, the Calibrated EMG-Informed Neuromusculoskeletal Modelling Toolbox (CEINMS), and Blender for visualization
• Collect data from a sample of four Australian Institute of Sport and Queensland Academy of Sport athletes and apply TDA-Aus model

Optimization and resilience-based strategies have been under-investigated in athletes, particularly in female athletes. This pilot project will assess mental, physical, hormonal, and immune measures of resilience in female athletes at three time points, capturing changes due to different stress loads (baseline, moderate load due to training/physical stress, high load due to combined academic and competitive stressors). Such knowledge will be valuable in developing a clinical intervention.

There is a high prevalence of Achilles overuse injuries in professional and recreational runners. This project’s objective is to develop a lightweight, unpowered ankle exosuit for running to reduce Achilles tendon loading. Such a device could reduce overuse injury risk and aid in recovery from Achilles overuse injuries (tendonitis, tendinopathy).

Their March 2025 publication in Journal of Biomechanical Engineering showed that their exoskeleton was able to reduce Achilles tendon loads by up to 12%.

Adequate recovery from exercise is a critical part of maintaining a high level of athletic performance. To withstand repetitive motion without degrading over time, tendons and ligaments undergo constant remodeling of the intricate extracellular matrix (ECM). Biological sex is a factor in the ability to maintain this healthy ECM, particularly in the musculoskeletal system, but the specific mechanisms and the relevant implications for functional recovery from exercise have not been explored.

This project focuses on the process of recovery from mechanical injury and how innate sex differences and hormones alter the ability to repair tissue structure. Previous studies have focused on collagen re-modeling as a primary mechanism of sex-related differences, but we hypothesize that turnover of other matrix proteins such as proteoglycans may hold the key to understanding estrous-cycle changes in mechanical function and recovery. Such knowledge would inform the development of preventative strategies and/or therapeutics to avoid injuries in the female athlete.

The meniscus of the knee joint is critical for knee health. It is prone to injuries, particularly in the region where it lacks blood supply, which unfortunately does not heal spontaneously. Surgical removal of the damaged meniscus, which is currently the standard of care, is a major risk factor for developing knee osteoarthritis. This study will test newly identified meniscus cells for their predicted ability to repair the damaged meniscus.

Muscle atrophy is a condition that impairs muscle function and performance, and results from a wide variety of conditions including disuse, aging, and nerve dysfunction. This project explores the potential of a novel form of therapy, mitochondrial transplantation therapy, to prevent muscle atrophy or enhance the recovery from atrophy in a preclinical mouse model of muscle disuse. Results from these studies have the potential to lead to novel approaches to preventing muscle dysfunction, enhancing recovery, and improving performance.

The Musculoskeletal Atlas Project (MAP) is a global open digital database of human skeletal and muscular information developed to enable rapid and accurate computational modelling of musculoskeletal biomechanics. This project aims to advance the MAP to enable truly multiscale musculoskeletal modelling and further the vision of developing digital athlete and digital human models for the future. It will do so by incorporating two types of data:

• Rodent data: Since the bulk of available data for microscale and molecular modelling of musculoskeletal tissue comes from rodent models, this project will incorporate new data and model standards and workflows being developed by the Alliance’s Molecular and Multiscale Athlete moonshots (RodeMAP) and the NIH-supported MoTrPAC datahub into the MAP.
• Human tendon: In collaboration with the Alliance’s Digital Athlete and Multiscale Athlete moonshots and the Triton Center for Injury and Performance Science, this project will extend the MAP to include high fidelity human tendon data and models of tissue state.

Tendinopathy, or tendon overuse injury, affects one in four people over the age of 40 and significantly limits exercise performance. In cases of chronic tendinopathy, the circadian rhythm normally observed in human tendons is dampened, likely affecting the tendon’s integrity and resulting in symptoms like pain and swelling.

Heavy Slow Resistance (HSR) exercise therapy is currently the most effective treatment for tendinopathy, but its exact impact on the tendon remains poorly understood. It’s been observed that exercise can synchronize the circadian rhythms in other parts of the body, such as muscles and fat. This project will investigate whether performing HSR exercise at specific times of the day can similarly synchronize the tendon’s circadian rhythm and optimize therapy outcomes.

Sleep and the synchronization of daily behaviors with the body’s internal clock (i.e., circadian alignment) are critical for optimal performance. Elite female athletes in sports such as the Women’s National Basketball Association (WNBA, USA) and Women’s National Basketball League (WNBL, Australia) often face unique challenges related to sleep and circadian disruption due to rigorous training schedules, multiple jobs, frequent travel, lack of resources (commercial vs-chartered flights) and competitive stress.

This research project will investigate the impact of sleep and circadian disruption on peak performance and recovery in elite female athletes, utilizing both existing data and data collected in a real-world longitudinal study. The multimethod assessment will be used to develop, implement, and test intervention programs to improve recovery and performance in an elite female athlete team. These studies will be the world’s first on sleep and circadian disruption in the WNBA and WNBL and will generate new knowledge on the physiological changes associated with acute and chronic sleep disruption.

The first results of this research were published in Nature Communications in April 2025. The study analyzed wearable data from over 14,000 physically active individuals. It shows that exercising at higher intensities and within 4 hours of sleeping are associated with several adverse effects, such as delayed sleep onset, shorter sleep duration, lower sleep quality, and higher nocturnal resting heart rate.

Anterior cruciate ligament (ACL) injuries of the knee is common and disproportionately affect amateur female athletes. These injuries often lead to reinjury, a lifetime reduction of physical activity, and early-onset osteoarthritis of the knee. Excessive inward bowing of the knees, referred to as “dynamic knee valgus” by biomechanists, when landing from a drop has been associated with an increased risk of ACL injury.

This project seeks to demonstrate that increased knee valgus during landing in amateur athletes is associated with worse neuromuscular control of the leg compared to elite athletes, providing a rigorous neuromechanical foundation to evaluate ACL injury risk. Such insights could inform new training approaches to mitigate the risk of ACL injuries.

Low Energy Availability (LEA) describes an energy mismatch between an individual’s dietary intake and the energy they use for physical activity. LEA can lead to a range of health problems and poor performance, under the broad umbrella of Relative Energy Deficiency in Sports (REDs). The prevention and treatment of REDs requires a better understanding of the complex nature of this crossover. This multi-disciplinary study tackles three major questions:

• Which body systems are most affected?
• Does the trigger of the energy mismatch matter? In other words, is it safer to restrict energy intake or to increase exercise?
• Do male and female athletes respond in the same way?

Examining the responses of different body systems to LEA will help identify where the potential risks lie and guide future interventional studies.

The goal of this research is to reveal key mappings between physiological states at the muscle level (e.g., muscle force, muscle shortening velocity) and optimal wearable robotic control. Such knowledge would provide a fundamental understanding of the constraints that limit elite human performance and also enable the design of devices that could assist athletes beyond their “human limits.” Achieving this goal involves the following:

• Create an open-source dataset of athletic tasks, performed by D1 athletes, in collaboration with the Alliance’s Digital Athlete Moonshot
• Develop deep learning models to estimate underlying human muscle dynamics from wearable sensors in athletes
• Optimize the relationship between deep human physiological states at the muscle level and optimal wearable robotic control across key athletic maneuvers such as running, jumping, and cutting performance

Circadian rhythms have a profound effect on metabolic processes and exercise performance, yet the molecular underpinnings of time-of-day variations in exercise outcomes are not yet understood.

This study aims to elucidate these variations in hormonal and metabolic responses to exercise in trained endurance athletes, with a particular focus on sex-specific variations. The analysis will integrate submaximal and maximal exercise performance metrics with multi-tissue metabolomic profiling of blood, skeletal muscle and adipose and also deep phenotypic characterization of athletes. The findings will not only enhance our understanding of the interactions between circadian biology and exercise metabolism, but also identify potential molecular targets for optimizing training and performance interventions tailored to the time of day and biological sex of the athlete.