The Role of GDF15 as a Myomitokine

Abstract

Growth differentiation factor 15 (GDF15) is a cytokine best known for affecting systemic energy metabolism through its anorectic action. GDF15 expression and secretion from various organs and tissues is induced in different physiological and pathophysiological states, often linked to mitochondrial stress, leading to highly variable circulating GDF15 levels. In skeletal muscle and the heart, the basal expression of GDF15 is very low compared to other organs, but GDF15 expression and secretion can be induced in various stress conditions, such as intense exercise and acute myocardial infarction, respectively. GDF15 is thus considered as a myokine and cardiokine. GFRAL, the exclusive receptor for GDF15, is expressed in hindbrain neurons and activation of the GDF15–GFRAL pathway is linked to an increased sympathetic outflow and possibly an activation of the hypothalamic-pituitary-adrenal (HPA) stress axis. There is also evidence for peripheral, direct effects of GDF15 on adipose tissue lipolysis and possible autocrine cardiac effects. Metabolic and behavioral outcomes of GDF15 signaling can be beneficial or detrimental, likely depending on the magnitude and duration of the GDF15 signal. This is especially apparent for GDF15 production in muscle, which can be induced both by exercise and by muscle disease states such as sarcopenia and mitochondrial myopathy.

Diltiazem inhibits breast cancer metastasis via mediating growth differentiation factor 15 and epithelial-mesenchymal transition

“…Glial cell-derived neurotrophic factor family receptor α-like (GFRAL) was describes as the sole receptor for GDF-15 [ 45 , 60 ], which is distantly related to TGF-β receptor family and was originally considered expressed in human brain stem exclusively [ 61 , 62 ]. With increasing evidence verifying the expression of GFRAL is also in cancer tissues, clues of GFRAL-independent effects of GDF-15 are also accumulating [ 63 – 65 ]. Nevertheless, further investigations are needed to elucidate these points.…”

The Potential Role of Growth Differentiation Factor 15 in COVID-19: A Corollary Subjective Effect or Not?

“…Mitochondrial stress and dysfunction are developed in response to abnormal immune responses and metabolic disturbances as in sepsis [ 77 ]. Under the effect of mitochondrial stress and dysfunction, various genes in cell survival are transcriptionally activated [ 78 ]. Mitochondrial stress triggers the release of various secretory proteins from cells such as the GDF15 and fibroblast growth factor 2, enabling cells with mitochondrial dysfunction to communicate with distant and neighboring cells to modulate the cell metabolism and energy [ 77 ].…”

Coping With Stress: The Mitokine GDF-15 as a Biomarker of COVID-19 Severity

“…Since, GDF-15 has been shown to be a cell-stress response cytokine produced in many cell types ( 7 ). Under physiological conditions, GDF-15 is expressed in high levels in the placenta, prostate, and bladder as well as other organs such as liver, kidney, lymph nodes, muscles and colon ( 14 , 15 ). Cell types reported to express GDF-15 include adipocytes, cardiomyocytes, skeletal and smooth muscle cells and macrophages ( 15 ).…”