Biology subjects

Heinemann-Yerushalmi, L.

Publications and source records attributed to Heinemann-Yerushalmi, L..

3 recordsLinked to original sources

bioRxiv2022

Molecular characterization of the intact muscle spindle using a multi-omics approach

The proprioceptive system is essential for the control of coordinated movement, posture and skeletal integrity. The sense of proprioception is produced in the brain using peripheral sensory input from receptors such as the muscle spindle, which detects changes in the length of skeletal muscles. Despite its importance, the molecular composition of the muscle spindle is largely unknown. In this study, we generated comprehensive transcriptomic and proteomic datasets of the entire muscle spindle. We then associated differentially expressed genes with the various tissues composing the spindle using bioinformatic analysis. Immunostaining verified these predictions, thus establishing new markers for the different spindle tissues. Utilizing these markers, we identified the differentiation stages the spindle capsule cells undergo during development. Together, these findings provide comprehensive molecular characterization of the intact spindle as well as new tools to study its development and function in health and disease.

developmental biology↗

bioRxiv2021

Neonatal enthesis healing involves non-inflammatory formation of acellular scar through ECM secretion by resident cells

Wound healing is a well-orchestrated process that typically recruits the immune and vascular systems to restore the structure and function of the injured tissue. Injuries to the enthesis, a hypocellular and avascular tissue, often result in fibrotic scar formation and loss of mechanical properties, thereby severely affecting musculoskeletal function and life quality. This raises questions about the healing capabilities of the enthesis. Here, we established an injury model to the Achilles entheses of neonatal mice to study the possibility that at an early age, the enthesis can heal more effectively. Histology and immunohistochemistry analyses revealed an atypical process that did not involve inflammation or angiogenesis. Instead, neonatal enthesis healing was mediated by secretion of collagen types I and II by resident cells, which formed a permanent hypocellular and avascular scar. Transmission electron microscopy showed that the cellular response to injury, including ER stress, autophagy and cell death, varied between the tendon and cartilage ends of the enthesis. Single-molecule in situ hybridization, immunostaining, and TUNEL assays verified these differences. Finally, gait analysis showed that these processes effectively restored function of the injured leg. Collectively, these findings reveal a novel healing mechanism in neonatal entheses, whereby local ECM secretion by resident cells forms an acellular ECM deposit in the absence of inflammation markers, allowing gait restoration. These insights into the healing mechanism of a complex transitional tissue may lead to new therapeutic strategies for adult enthesis injuries.

molecular biology↗

bioRxiv2020

BCKDK regulates the TCA cycle through PDC to ensure embryonic development in the absence of PDK family

Pyruvate dehydrogenase kinases (PDK1-4) inhibit the TCA cycle by phosphorylating pyruvate dehydrogenase complex (PDC). Here, we show that the PDK family is dispensable for the survival of murine embryonic development and that BCKDK serves as a compensatory mechanism by inactivating PDC. First, we knocked out all four Pdk genes one by one. Surprisingly, Pdk total KO embryos developed and were born in expected ratios, but died by postnatal day 4 due to hypoglycemia or ketoacidosis. Finding that PDC was phosphorylated in these embryos suggested that another kinase compensates for the PDK family. Bioinformatic analysis implicated brunch chain ketoacid dehydrogenase kinase (Bckdk), a key regulator of branched chain amino acids (BCAA) catabolism. Indeed, knockout of Bckdk and the Pdk family led to loss of PDC phosphorylation, increment in PDC activity, elevation of Pyruvate flux into the TCA and early embryonic lethality. These findings reveal a new regulatory crosstalk hardwiring BCAA and glucose catabolic pathways, which feed the TCA cycle.

molecular biology↗