The erythropoietin receptor expressed in skeletal muscle is essential for mitochondrial biogenesis and physiological exercise

Kirsten T. Nijholt, Laura M. G. Meems, Willem P. T. Ruifrok, Alexander H. Maass, Salva R. Yurista, Mario G. Pavez-Giani, Belend Mahmoud, Anouk H. G. Wolters, Dirk J. van Veldhuisen, Wiek H. van Gilst, Herman H. W. Sillje, Rudolf A. de Boer, B. Daan Westenbrink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Erythropoietin (EPO) is a haematopoietic hormone that regulates erythropoiesis, but the EPO-receptor (EpoR) is also expressed in non-haematopoietic tissues. Stimulation of the EpoR in cardiac and skeletal muscle provides protection from various forms of pathological stress, but its relevance for normal muscle physiology remains unclear. We aimed to determine the contribution of the tissue-specific EpoR to exercise-induced remodelling of cardiac and skeletal muscle. Baseline phenotyping was performed on left ventricle and m. gastrocnemius of mice that only express the EpoR in haematopoietic tissues (EpoR-tKO). Subsequently, mice were caged in the presence or absence of a running wheel for 4 weeks and exercise performance, cardiac function and histological and molecular markers for physiological adaptation were assessed. While gross morphology of both muscles was normal in EpoR-tKO mice, mitochondrial content in skeletal muscle was decreased by 50%, associated with similar reductions in mitochondrial biogenesis, while mitophagy was unaltered. When subjected to exercise, EpoR-tKO mice ran slower and covered less distance than wild-type (WT) mice (5.5 +/- 0.6 vs. 8.0 +/- 0.4 km/day, p < 0.01). The impaired exercise performance was paralleled by reductions in myocyte growth and angiogenesis in both muscle types. Our findings indicate that the endogenous EPO-EpoR system controls mitochondrial biogenesis in skeletal muscle. The reductions in mitochondrial content were associated with reduced exercise capacity in response to voluntary exercise, supporting a critical role for the extra-haematopoietic EpoR in exercise performance.

Original languageEnglish
Number of pages13
JournalPflügers Archiv : European Journal of Physiology
DOIs
Publication statusPublished - 17-Jun-2021

Keywords

  • Erythropoietin receptor
  • Cardiac and skeletal muscle
  • Mitochondrial biogenesis
  • Exercise performance
  • Exercise-induced physiological adaptation
  • RECOMBINANT-HUMAN-ERYTHROPOIETIN
  • CARDIAC-FUNCTION
  • HEART-FAILURE
  • MICE
  • DIFFERENTIATION
  • PGC-1-ALPHA
  • ISCHEMIA
  • CAPACITY
  • PROTEIN
  • VOLUME

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