Biology subjects

Mlawer, S. J.

Publications and source records attributed to Mlawer, S. J..

4 recordsLinked to original sources

bioRxiv2026

Aged Tendons Have Impaired Mechanosensitivity and Lower Thresholds for Injury under Dynamic Compression

Rotator cuff tendinopathy is highly prevalent in aging populations, yet the mechanisms leading to age-dependent tendon degeneration are not well understood. In addition to tensile loading, tendons are subjected to compressive forces at certain anatomical sites (e.g., Achilles, rotator cuff), where altered adaptive responses may contribute to degenerative remodeling. The objective of this study was to investigate age-related differences in tendon responses to dynamic compressive loading using an ex vivo model. Murine flexor tendon explants from young and aged animals were cultured in a biaxial bioreactor and subjected to different levels of dynamic compressive loading. We then observed changes in metabolic activity, matrix composition, matrix biosynthesis, matrix structure, and gene expression. Young tendons exposed to moderate levels of compression maintained homeostasis, whereas high compression induced a robust adaptive response characterized by increased glycosaminoglycan accumulation, elevated collagen content, and upregulation of remodeling-associated genes including collagen I, decorin, and MMP-9, as well as inflammatory and apoptotic markers. In contrast, aged tendons demonstrated a qualitatively different response, with transcriptional downregulation of key remodeling markers alongside elevated secretion of matrix-degrading enzymes and pro-inflammatory cytokines, indicative of a maladaptive mechanobiological response even at low compressive levels. These findings reveal that impaired mechanosensitivity and a lower threshold for injury may predispose chronically loaded tissues to degenerative pathology associated with excessive compressive loading.

bioengineering↗

bioRxiv2024

Coordination of Glucose and Glutamine Metabolism in Tendon is Lost in Aging

Tendinopathy is an age-associated degenerative disease characterized by a loss in extracellular matrix (ECM). Since glucose and glutamine metabolism is critical to amino acid synthesis and known to be altered in aging, we sought to investigate if age-related changes in metabolism are linked to changes in ECM remodeling. We exposed young and aged tendon explants to various concentrations of glucose and glutamine to observe changes in metabolic processing (enzyme levels, gene expression, etc.) and matrix biosynthesis. Interestingly, we found that glutamine processing is affected by glucose levels, but this effect was lost with aging. ECM synthesis was altered in a protein-dependent manner by increased glucose and glutamine levels in young tendons. However, these changes were not conserved in aged tendons. Overall, our work suggests that glucose and glutamine metabolism is important for ECM homeostasis, and age-related changes in nutrient metabolism could be a key driver of tendon degeneration.

bioengineering↗

bioRxiv2024

Aged Tendons Exhibit Altered Mechanisms of Strain-Dependent Extracellular Matrix Remodeling

Aging is a primary risk factor for degenerative tendon injuries, yet the etiology and progression of this degeneration is poorly understood. While aged tendons have innate cellular differences that support a reduced ability to maintain mechanical tissue homeostasis, the response of aged tendons to altered levels of mechanical loading has not yet been studied. To address this question, we subjected young and aged murine flexor tendon explants to various levels of in vitro tensile strain. We first compared the effect of static and cyclic strain on matrix remodeling in young tendons, finding that cyclic strain is optimal for studying remodeling in vitro. We then investigated the remodeling response of young and aged tendon explants after 7 days of varied mechanical stimulus (stress-deprivation, 1%, 3%, 5%, or 7% cyclic strain) via assessment of tissue composition, biosynthetic capacity, and degradation profiles. We hypothesized that aged tendons would show muted adaptive responses to changes in tensile strain and exhibit a shifted mechanical setpoint, at which the remodeling balance is optimal. Interestingly, we found 1% cyclic strain best maintains native physiology while promoting ECM turnover for both age groups. However, aged tendons display fewer strain-dependent changes, suggesting a reduced ability to adapt to altered levels of mechanical loading. This work has significant impact in understanding the regulation of tissue homeostasis in aged tendons, which can inform clinical rehabilitation strategies for treating elderly patients.

bioengineering↗

bioRxiv2022

The Micromechanical Environment of the Impinged Achilles Tendon Insertion

Mechanical deformation applied to tendon at the tissue-scale is transferred to the microscale -- including the extracellular matrix (ECM), the pericellular matrix (PCM), the cell and the nucleus -- through a process known as strain transfer. Microscale strains, in turn, trigger biological activity that plays an important role in the maintenance of tendon phenotype and homeostasis. Although tendon predominantly experiences longitudinal tensile forces, transverse forces due to bony impingement have been implicated in both physiological (e.g., maintenance of the tendon insertion) and pathophysiological (e.g. insertional Achilles tendinopathy) processes. However, to our knowledge, prior studies have not characterized the micromechanical strain environment in the context of tendon impingement. Therefore, the objective of this study was to characterize the micromechanical strain environment in the impinged Achilles tendon insertion using a novel mouse hindlimb explant model in combination with finite element (FE) modeling. We hypothesized that impingement would generate large magnitudes of transverse compressive strain at the local matrix, PCM, and cell scales. Mouse hindlimb explants were imaged on a multiphoton microscope, and image stacks of the same population of tendon cells were obtained at the Achilles tendon insertion before and after dorsiflexion-induced impingement. Using an innovative multiphoton elastography approach, three-dimensional Green-Lagrange and principal strains were measured at the matrix scale, while longitudinal strain and aspect ratio were measured at the PCM and cell scales. Our results demonstrate that impingement generated substantial transverse compression at the matrix-scale, which led to longitudinal stretching of cells, an increase in cell aspect ratio, and -- surprisingly -- longitudinal compression of the tendon PCM. These experimental results were corroborated by an FE model developed to simulate the micromechanical environment in impinged regions of the Achilles tendon. Moreover, in both experiments and simulations, impingement-generated microscale stresses and strains were highly dependent on initial cell-cell gap spacing. Understanding the factors that influence the microscale strain environment generated by impingement could contribute to a more mechanistic understanding of impingement-induced tendinopathies and inform the development of approaches that disrupt the progression of pathology.

bioengineering↗