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Abstract
Maintaining skeletal muscle and bone integrity requires movement, more specifically mechanical strain and/or load. Habitual strain from skeletal muscles is a chief regulator of bone anisotropy, mechanically and functionally linking the two tissues. The musculoskeletal unit (muscle and adjacent long bone) is mechanosensitive and tends to scale together depending on the magnitude of load or strain. Consequently, prolonged states of inactivity or unloading results in a loss of muscle mass (muscle atrophy) and function, as well as bone reabsorption, leading to an increased fracture risk. Traumatic muscle injuries are represented by the physical loss or ablation of skeletal muscle tissue (~15%). Unfortunately, the standard of care for traumatic injuries (soft-tissue, fractures, and polytrauma) has not been established. Surprisingly, few investigations have explored the influence of volumetric muscle loss injury on the adjacent long bone, despite much supporting evidence of the mechanistic link. I designed and executed experimental investigations uncovering bone maladaptation following volumetric muscle loss injury. Furthermore, we explore and implement physical rehabilitation strategies to bolster muscle regeneration following volumetric muscle loss injury. Lastly, we implement a novel combinatorial approach of physical rehabilitation and an implantable biomaterial to optimize mechanotransduction. Our results of altered bone geometry and function following volumetric muscle loss injury (Schifino et al., 2023) are supported by the mechanostat theory. Indeed, lower peak muscle torque was associated with altered tibial bone geometry and reduced fracture resistance following VML injury in mice (Chapter 3). We include an investigation of clinically translatable rehabilitation approaches (resistance wheel running & whole-body vibration) and the influence on muscle (Chapter 4), and bone structure and function (Chapter 5). Lastly, we conclude with insights from a combination of biomaterials and physical rehabilitation to leverage mechanotransduction to influence muscle and bone. Our findings support the need for combinatorial approaches, as clearly leveraging mechanotransduction alone is not sufficient to overcome the limited endogenous regenerative capacity of skeletal muscle. Despite collective efforts on many fronts: activate satellite cells, mitigate fibrosis, bolster transcriptional response, traffic cells, and nanomaterials, or physically support with scaffolds or biomaterials, complete functional recovery remains elusive.