Muscle wasting associated with the long-term use of mTOR inhibitors

Abstract

Some targeted therapies alter muscle mass due to interference with pathways of muscle metabolism. The effects of mammalian target of ra pamycin (mTOR) inhibitors on muscle mass have yet to be fully elucidated. In the present study, the computerized tomography (CT) scans of patients receiving mTOR inhibitors for at least 6 months taken at baseline and post-therapy were retrospectively retrieved, and body composition analyses were performed using the software, sliceOmatic version 5.0 (TomoVision, Inc., Magog, QC, Canada). The difference in body composition parameters was evaluated for significance. The time to treatment (TTF) failure was also compared between the sarcopenic and non-sarcopenic patients at the baseline. Of the 75 patients studied, 20 matched the inclusion criteria (including 16 males). The mean duration between the CT scans was 14.4±2.0 months. A total of 12 (60%) patients were sarcopenic at the baseline, whereas three more (75% in total) became sarcopenic following treatment. The use of mTOR inhibitors significantly decreased the skeletal muscle area (P=0.011) and lean body mass (P=0.007), although it had no effect on adipose tissue (P=0.163) or body weight (P=0.262). The rate of skeletal muscle wasting was 2.6 cm/m, or 2.3 kg in 6 months. The TTF did not differ between sarcopenic and non-sarcopenic patients, and was not significantly associated with any other parameter. To the best of our knowledge, this is the first study to demonstrate that the long-term use of mTOR inhibitors induces a marked loss of muscle mass. Due to the predictive and prognostic role of sarcopenia in cancer patients, these findings may have important clinical implications.

Dietary intake of probiotic kimchi ameliorated IL-6-driven cancer cachexia

“…First, encouraging mTOR and AKT signaling to overcome sarcopenia with adalimumab, silver linings on the horizon by Ebner & Haehling, (42) is recommended since long-term use of mTOR inhibitors led to a marked loss of muscle mass. (43) As summarized by several investigators (44)(45)(46) and ours in the current study ( Fig. 6), molecular substrates and mechanisms underlying the dysregulation of skeletal muscle synthesis and degradation included proinflammatory cytokines such as TNF-a, IL-1, IL-6 and related signaling transduction systems such as NF-kB, MAPKs, acute phase reactants, and myostatin-activin-SMAD pathways.…”

Lean body mass wasting and toxicity in early breast cancer patients receiving anthracyclines

“…Several studies showed that the decrease of LBM is associated with higher chemotherapy toxicities, as well as a worse outcome in various cancer type [ 5 , 15 – 40 ]. Moreover, a muscle wasting without adipose tissue and body weight reduction was observed during anticancer treatment with both chemotherapy and target therapy [ 25 , 41 ]. Focusing on studies conducted on breast cancer, Prado and colleagues published a study performed on 55 metastatic patients treated with capecitabine, evaluating muscle mass by CT scans at L3 vertebra level.…”

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

“…Targeting mTORC1 signalling is the only therapeutic avenue yet explored for laminopathies that has promise against both dystrophic and progeroid laminopathies [137], but it has yet to be tested in sarcopenia. However, as a note of caution, patients taking rapamycin for more than 6 months for treatment of renal cell carcinoma or paracrine neuroendocrine tumours demonstrated an increase in sarcopenia [138], a worrying finding as sarcopenia is predictive of outcomes in cancer patients. Longitudinal rapamycin studies in healthy subjects, such as those ongoing in companion dogs [139] are needed to inform on whether low dose mTOR inhibition may be able to delay or even prevent the onset of sarcopenia.…”