Kairui Zhang1,2, Michael W Hast3, Soutarou Izumi4, Yu Usami2,5, Snehal Shetye3, Ngozi Akabudike4, Nancy J Philp6, Masahiro Iwamoto2,4, Itzhak Nissim7, Louis J Soslowsky3, Motomi Enomoto-Iwamoto2,4. 1. Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, China. 2. Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 3. McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 4. Department of Orthopaedics, University of Maryland, Baltimore, Maryland, USA. 5. Department of Oral Pathology, Osaka University, Osaka, Japan. 6. Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. 7. Division of Metabolism and Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Abstract
BACKGROUND: Tendon injuries are common problems among athletes. Complete recovery of the mechanical structure and function of ruptured tendons is challenging. It has been demonstrated that upregulation of glycolysis and lactate production occurs in wounds, inflammation sites, and cancerous tumors, and these metabolic changes also control growth and differentiation of stem and progenitor cells. Similar metabolic changes have been reported in human healing tendons. In addition, lactate production has increased in progenitors isolated from injured tendons after treatment with IL-1β. It is thought that the metabolic changes play a role in tendon healing after injury. HYPOTHESIS: Glucose metabolism is altered during tendon injury and healing, and modulation of this altered metabolism improves tendon repair. STUDY DESIGN: Controlled laboratory study. METHODS: The authors used the tendon injury model involving a complete incision of the Achilles tendon in C57BL/6J female mice and studied alterations of glucose metabolism in injured tendons with [U-13C]glucose and metabolomics analysis 1 and 4 weeks after surgery. They also examined the effects of dichloroacetate (DCA; an indirect lactate synthesis inhibitor) treatment on the recovery of structure and mechanical properties of injured tendons 4 weeks after surgery in the same mouse model. RESULTS: Significant changes in glucose metabolism in tendons after injury surgery were detected. 13C enrichment of metabolites and intermediates, flux through glycolysis, and lactate synthesis, as well as tricarboxylic acid cycle activity, were acutely increased 1 week after injury. Increased glycolysis and lactate generation were also found 4 weeks after injury. DCA-treated injured tendons showed decreased cross-sectional area and higher values of modulus, maximum stress, and maximum force when compared with vehicle-treated injured tendons. Improved alignment of the collagen fibers was also observed in the DCA group. Furthermore, DCA treatment reduced mucoid accumulation and ectopic calcification in injured tendons. CONCLUSION: The findings indicate that injured tendons acutely increase glycolysis and lactate synthesis after injury and that the inhibition of lactate synthesis by DCA is beneficial for tendon healing. CLINICAL RELEVANCE: Changing metabolism in injured tendons may be a therapeutic target for tendon repair.
BACKGROUND: Tendon injuries are common problems among athletes. Complete recovery of the mechanical structure and function of ruptured tendons is challenging. It has been demonstrated that upregulation of glycolysis and lactate production occurs in wounds, inflammation sites, and cancerous tumors, and these metabolic changes also control growth and differentiation of stem and progenitor cells. Similar metabolic changes have been reported in human healing tendons. In addition, lactate production has increased in progenitors isolated from injured tendons after treatment with IL-1β. It is thought that the metabolic changes play a role in tendon healing after injury. HYPOTHESIS: Glucose metabolism is altered during tendon injury and healing, and modulation of this altered metabolism improves tendon repair. STUDY DESIGN: Controlled laboratory study. METHODS: The authors used the tendon injury model involving a complete incision of the Achilles tendon in C57BL/6J female mice and studied alterations of glucose metabolism in injured tendons with [U-13C]glucose and metabolomics analysis 1 and 4 weeks after surgery. They also examined the effects of dichloroacetate (DCA; an indirect lactate synthesis inhibitor) treatment on the recovery of structure and mechanical properties of injured tendons 4 weeks after surgery in the same mouse model. RESULTS: Significant changes in glucose metabolism in tendons after injury surgery were detected. 13C enrichment of metabolites and intermediates, flux through glycolysis, and lactate synthesis, as well as tricarboxylic acid cycle activity, were acutely increased 1 week after injury. Increased glycolysis and lactate generation were also found 4 weeks after injury. DCA-treated injured tendons showed decreased cross-sectional area and higher values of modulus, maximum stress, and maximum force when compared with vehicle-treated injured tendons. Improved alignment of the collagen fibers was also observed in the DCA group. Furthermore, DCA treatment reduced mucoid accumulation and ectopic calcification in injured tendons. CONCLUSION: The findings indicate that injured tendons acutely increase glycolysis and lactate synthesis after injury and that the inhibition of lactate synthesis by DCA is beneficial for tendon healing. CLINICAL RELEVANCE: Changing metabolism in injured tendons may be a therapeutic target for tendon repair.
Authors: Yanming Bi; Driss Ehirchiou; Tina M Kilts; Colette A Inkson; Mildred C Embree; Wataru Sonoyama; Li Li; Arabella I Leet; Byoung-Moo Seo; Li Zhang; Songtao Shi; Marian F Young Journal: Nat Med Date: 2007-09-09 Impact factor: 53.440
Authors: Jessica E Ackerman; Michael B Geary; Caitlin A Orner; Fatima Bawany; Alayna E Loiselle Journal: PLoS One Date: 2017-07-07 Impact factor: 3.240
Authors: Philipp A Michel; Daniel Kronenberg; Gertje Neu; Josef Stolberg-Stolberg; Andre Frank; Thomas Pap; Martin Langer; Michael Fehr; Michael J Raschke; Richard Stange Journal: J Orthop Translat Date: 2020-05-11 Impact factor: 5.191