Effects of tyrosine kinase inhibitors on skeletal muscle metabolism: a link with muscle complaints

Abstract

Chronic myeloid leukemia (CML) patients receiving tyrosine kinase inhibitors (TKIs) often report muscle complaints (MC). Strategies to prevent or attenuate these muscle complaints remain enigmatic as the underlying mechanism is unclear, although a central role for mitochondria is proposed. We investigated the effects of TKIs on cellular metabolism in muscle biopsies of CML patients ( n = 20), compared with healthy controls ( n = 10) and whether these changes may be linked to muscle complaints. C2C12 myotubes were used to further explore the effects of TKIs on muscle metabolism in vitro. We found that TKI muscle concentrations in CML patients aligned with the concentrations at which cytotoxicity could be observed in C2C12 myotubes, and that muscle to plasma ratios tended to correlate with the degree of MC in CML patients. In C2C12 myotubes, acute TKI incubation of C2C12 myotubes resulted in alterations in energy metabolism, showing a shift from glycolysis to oxidative phosphorylation. CML patients without MC showed higher oxidative capacity, characterized by higher mitochondrial complex activities in skeletal muscle and occurrence of the first ventilatory threshold at a higher percentage of peak oxygen uptake during maximal exercise compared to patients with MC. Taken together, these observations raise the possibility that TKIs may affect cellular energy metabolism and may contribute to muscle complaints. Trial registration The Netherlands Trial Registry identifier NTR6373.

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