Lumbar spine (LS) problems are the number one cause for medical encounters and lost work time among military personnel. This has been associated with the heavy loads carried during operational duties. Consequently, the effect of load carriage on military performance has been studied extensively. However, LS postural adaptations during load carriage have not been described. Thus, the overall goal of this dissertation is to understand in vivo LS postural response to load carriage in active duty Marines.

This dissertation begins with a feasibility study to demonstrate that LS postural differences between unloaded and loaded tasks are measurable in vivo using an upright magnetic resonance imaging (MRI) scanner. Increased lumbar flexion and reduced lordosis were measured during loaded tasks. In Chapter 3 we examined LS response to load carriage as Marines progressed through the School of Infantry (SOI) Training. Although no effect of training was observed, we found that Marines with disc degeneration carried loads slightly different.

These results suggested that load characteristics determined load carriage posture of the LS, regardless of Marines physical fitness. Therefore, in Chapter 4 we explored the interaction between operationally relevant load magnitudes and distributions on LS posture. Specifically, balancing loads in the anterior-posterior direction yielded lumbar spine postures that are nearly identical to standing. Contrastingly, when load was carried with a posterior bias, superior LS lordosis increased as a function of load magnitude, while inferior LS lordosis was distribution dependent.

These data represent the first in vivo measurements of LS posture under operationally relevant loads. The key findings are: 1) lumbar lordosis is reduced as the spine and hips are flexed forward, 2) improving strength and endurance through training does not appear to change LS behavior during load carriage, and 3) manipulating the load magnitude and distribution does yield significant changes in LS behavior.

Clinically and operationally, these findings are significant because they provide direct, quantitative data that can be used to make informed decisions about load carriage recommendations. Future work may include a longitudinal study to test whether balanced loads prevent injury or enhance operational efficiency in the military.

Rotator cuff tears affect 1 in 5 individuals over the age of 60, leading to muscle atrophy, degeneration, fibrosis, and fatty infiltration. These changes observed in muscle are persistent regardless of treatment or surgical repair, and the progression to this irreversible degenerative muscle state is poorly understood. The purpose of this work was to investigate the temporal histological and transcriptomic behavior of biological programs after rotator cuff tear and repair in a rabbit model. We performed RNAseq at 1, 2, 4, 8, and 16 weeks after tear and 1, 2, 4, and 8 weeks after repair to identify the transcriptional profile of biological programs (i.e. inflammation, adipogenesis, apoptosis). After detecting a strong immune system signature, we evaluated the number of immune cells and markers of proliferation/cell cycle histologically. Post-tenotomy there was a clear orchestration of biological programs largely related to inflammation and energetics at early timepoints, a progression towards adipogenesis and apoptosis that subsided by 8 weeks, and a resurgence of various programs including inflammation, fibrosis, and apoptosis at 16 weeks. Post-repair there was a lack of a regenerative response to mechanical re-loading, but instead, a strong resurgence of inflammation, adipogenesis, fibrosis and apoptosis at 2 weeks that subsided by 8 weeks. Relative to the immune system, there was a significant increase in neutrophil numbers at 1 and 4 weeks post-tenotomy, but few to none post-repair. There was a significant increase in CD163+ macrophages at 2 week post-tenotomy and 1 and 2 weeks post-repair. This increase was also seen regionally post-repair, with more CD163+ (M2c) macrophages found in regions of muscle degeneration compared to regions of non-degenerated muscle at almost all timepoints (1, 2, 4 weeks). In conclusion, we identified a temporal transcriptional profile of biological programs such as inflammation, adipogenesis and fibrosis and highlighted contrasting immune system behaviors of neutrophils and CD163+ macrophages in muscle after rotator cuff tear and repair. These data provide a time-resolved framework for understanding myocyte-inflammatory cell- progenitor cell interactions that are poorly understood in muscle. Translationally, these data provide context for transcriptional and cell-based assays of human tissue that can only be procured cross-sectionally in time, and they shed light onto potential therapeutic targets that may augment muscle recovery after tendon repair in patients with rotator cuff injuries.

Rotator cuff (RC) tears are a degenerative condition that affects ~30% of people over the age of 60, resulting in pain and loss of function in the shoulder. Chronically torn muscles are prone to atrophy, fatty infiltration, and an increase in tissue stiffness. These changes are insensitive to rehabilitation and are associated with poor patient and surgical outcomes.

Although human clinical studies of RC tears are common, they are limited by a lack of experimental control and logistical difficulties. Thus, animal models have been utilized to study this injury. However, data describing the muscle architecture and mechanics in these models are limited. Therefore, in chapter 2, we characterized muscle architectural adaptations in a rat model of RC injury. We discovered that tenotomy alone leads to mild changes in muscle architecture, while adding a secondary chemical nerve injury causes extensive muscle changes.

Various studies have demonstrated increased passive stiffness of the whole muscle after RC tear, but the mechanisms causing this phenomenon were unknown. Therefore, in Chapter 3, we measured stiffness at the individual fiber and fiber bundle levels. Fiber bundles stiffness increased after a combined tendon and nerve injury, but was unchanged after tenotomy alone. These results suggest that stiffness changes are due to adaptations in the extracellular matrix.

Recent studies have reported functional deficits in tenotomized RC muscles that are not predicted by architectural adaptations. A potential explanation for this could be that muscle strain to sarcomere strain transmission is altered after injury. In chapter 4, we investigated this discrepancy and found that strain transmission was not altered due to tenotomy at low strains. However, sarcomere lengths were significantly shorter in tenotomized muscles at high strains. These results fail to predict the presence of functional deficits in tenomized muscles and do not reconcile the reported deficits.

Overall, these data suggest that this model of RC injury exhibits mild changes that are not representative of the human injury. Future research may need to pursue alternative models (aged animals, alternative species, etc.) of RC tear that result in muscle adaptations that are comparable to what is observed in human patients.

Low back pain (LBP) is a common musculoskeletal complaint, and is a particularly large problem in the military. Heavy load carriage and unusual postures military members operate under in training and in combat have been implicated as primary causes of LBP. The muscles of the lumbar spine (LS) are crucial for providing stability and maintaining posture; lumbar instability is associated with chronic LBP and can result in injury. With injury and age, degenerative structural changes in muscle tissue are observed in concert with gross alterations in posture, however the relationship between muscle microstructure and posture isn’t well understood. The purpose of these studies was to investigate the predictive capacity of muscle structure on LS posture in active-duty Marines under operationally relevant conditions. Fractional anisotropy, a measure of muscle microstructure made with diffusion tensor imaging (DTI), was found to be a key predictor of LS posture. Trying to translate these findings to physiologic measures of muscle, it became evident that DTI is nonspecific to individual features of muscle microstructure. To address this gap in our understanding of skeletal muscle DTI’s capacity to non-invasively quantify muscle microstructure, we sought to establish an accurate and precise, DTI based tool to measure individual components of muscle microstructure. To achieve this goal we used in silico-based simulation to create a theoretical framework between DTI and key features of muscle microstructure. A precision engineered, nano-fabricated diffusion phantom was developed and tested to validate this framework in real world experiments. The main findings from these studies were the DT is most sensitive to fiber size under 60μm diameter. Using this framework to interpret the relationship between muscle microstructure and posture, Marines with smaller muscle fibers in the erector spinae muscle group have decreased lumbar lordosis, decreased lumbar extension and decreased sacral slope. Clinically and operationally, these findings are significant because they provide the framework for a non-invasive tool that can be used to measure and predict maladaptive posture in operational conditions from musculoskeletal health, which could allow clinicians to tailor rehabilitation protocols to prevent injury, and potentially be used to predict an individual’s risk for LS injury.

More than 30% of the population over age 60 will suffer from a rotator cuff tear. Progressive tears lead to atrophic and degenerative muscle changes that persist irrespective of therapeutic intervention, whether conservative or surgical. The degree of decreased muscle quality (retraction, atrophy, fibrosis, and fatty degeneration) serves as the strongest predictor of post-surgical functional outcomes, yet the quantitative effects on muscle physiology are poorly understood. The purpose of this work was to investigate the structural and functional implications of rotator cuff tear and repair in a rabbit model system. We first established a method to evaluate the structure-function relationship in healthy supraspinatus muscles. We then performed a detailed architectural analysis to relate the structural and physiological consequences of rotator cuff tear and repair. Finally, we evaluated the activation of mechanotransduction pathways in our model system to investigate a potential mechanism for persistent muscle loss. In summary, we characterized aspects of the altered structure-function relationship in both torn and surgically repaired rotator cuff muscles to better understand the physiological implications of disease and potential therapies.

One in five people have a rotator cuff tear, increasing with age to 50% of patients in the eighth decade of life. This creates a large burden on the healthcare system, as outcomes of tendon repair are poor and functional recovery even after successful tendon repair is limited. Strongly associated with rotator cuff tendon tears are irreversible muscle loss and muscle fatty infiltration, which serve as key clinical indicators of disease progression and predictors of surgical outcome. The prevailing biological and treatment paradigms have attributed these negative muscle changes to atrophy and subsequent space-filling by adipocytes. However, atrophy is a well-defined, self-limiting, and generally reversible response to unloading, which does not adequately explain the irreversibility of muscle loss in these patients. In human muscle biopsies, we discovered a novel phenotype of muscle fiber degeneration in which segments of muscle fiber membranes and cytoplasm are disrupted, leading to alternately hyper- and hypo-cellular degenerative regions. While muscle regeneration is increased in these biopsies, in some cases degenerative regions appear to resolve by adipocyte deposition within the fascicular architecture in a process of fatty replacement. Together with our finding that sarcomeres remodel normally in full-thickness but not massive tears, these data provide a compelling explanation for irreversibility of muscle loss in chronic, massive tears; total muscle volume is permanently reduced over time, and the remaining muscle is no longer sensitive to mechanical loading. After exhaustive characterization of small- and large-animal models of RCT in the context of these human findings, we determined that rabbit and sheep each adequately recapitulate the tissue-level degenerative processes found clinically. Using these models, we have begun to define the biological processes involved in chronic muscle degeneration, which include cellular stress and membrane damage responses, inhibition of growth and metabolism (particularly oxidative phosphorylation), prolonged inflammation, and competing processes of cell death and survival, while protein catabolic processes commonly associated with atrophy are notably absent. In conclusion, the findings of muscle degeneration and replacement of muscle fibers with adipose tissue described here provide a new paradigm for understanding and treating muscle loss in chronic rotator cuff disease.

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