MT‐102 prevents tissue wasting and improves survival in a rat model of severe cancer cachexia

Abstract

Background Cachexia, a common manifestation of malignant cancer, is associated with wasting of skeletal muscle and fat tissue. In this study, we investigated the effects of a new first in class anabolic catabolic transforming agent on skeletal muscle in a rat model of cancer cachexia. Methods Young male Wistar Han rats were intraperitoneally inoculated with 10 8 Yoshida hepatoma AH-130 cells and once daily treated with 0.3 mg kg À1 , 3 mg kg À1 MT-102, or placebo by gavage. Results Three mg kg À1 d À1 MT-102 not only prevented progressive loss of fat mass (À6 ± 2 g vs -12 ± 1 g; P < 0.001); lean mass (+1 ± 10 g vs. À37 ± 2 g; P < 0.001) and body weight (+1 ± 13 g vs. À60 ± 2 g; P < 0.001) were remained. Quality of life was also improved as indicated by a higher food intake 12.9 ± 3.1 g and 4.3 ± 0.5 g, 3 mg kg À1 d À1 MT-102 vs. placebo, respectively, P < 0.001) and a higher spontaneous activity (52 369 ± 6521 counts/24 h and 29 509 ± 1775 counts/24 h, 3 mg·kg -1 d -1 MT-102 vs. placebo, respectively, P < 0.01) on Day 11. Most importantly, survival was improved (HR = 0.29; 95% CI: 0.16-0.51, P < 0.001). The molecular mechanisms behind these effects involve reduction of overall protein degradation and activation of protein synthesis, assessed by measurement of proteasome and caspase-6 activity or Western blot analysis, respectively. Conclusions The present study shows that 3 mg kg À1 MT-102 reduces catabolism, while inducing anabolism in skeletal muscle leading to an improved survival.

Small-Molecule Chemical Knockdown of MuRF1 in Melanoma Bearing Mice Attenuates Tumor Cachexia Associated Myopathy

“…With regard to fat metabolism, transgenic MuRF1 mouse studies have implicated MuRF1 in the regulation of fat metabolism via pyruvate dehydrogenases (PDH) and pyruvate dehydrogenase kinase (PDK)-4 [ 52 ]. Since the used [2-oxo-chromen-7-yl) heteromethyl]benzoic acids are not related to other known drug classes, it also remains to be determined if co-treatment strategies may be warranted, such as with MT-102 that was recently reported to provide benefits to cancer cachexia by targeting the adrenergic system [ 53 ]. Future studies have to identify the exact molecular mechanisms of how MyoMed-205 or MyoMed-946 provoke the beneficial effect seen in several muscle-wasting conditions, such as pulmonary hypertension [ 22 ], chronic heart failure [ 23 ], and cancer cachexia.…”

Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments

“…Thus, the preservation of muscle tissue may contribute to prolonged lifespan per se. This is supported by a large body of evidence showing that different strategies able to prevent muscle wasting in cancer cachexia result in improved survival [10][11][12][103][104][105][106][107]109,110,146,178,179]. It is possible that the preservation of some vital muscles, such as the major respiratory muscles, plays an important role in survival [100,101].…”

“…In support of a causal link between cachexia and mortality, prevention of muscle wasting has been associated with improved survival in a number of pre-clinical murine models of cancer cachexia [10][11][12][13][103][104][105][106][107][108][109]. Inhibition of nuclear factor-κB (NF-κB) signaling in muscle [104] or tumour necrosis factor (TNF)-like weak inducer of apoptosis/ fibroblast growth factor-inducible 14 (TWEAK/Fn14) signaling in the tumor [106], block-ade of growth differentiation factor 15 (GDF15) [107], treatment with histone deacetylase inhibitors [109], or counteraction of myostatin and activins [10][11][12][13]105,110] have resulted in prevention of muscle wasting and improved survival in different murine models of cancer cachexia.…”

Muscle Wasting and Sarcopenia in Heart Failure—The Current State of Science

“…Most importantly, survival was significantly improved (HR: 0.29, 95% CI: 0.16-0.51, p < 0.001). Mechanistically, espindolol reduces catabolic signaling (reduced myostatin, ubiquitin proteasome system (UPS) activity, autophagy), while increasing anabolic signaling (Protein kinase B, Akt/mTOR) [111]. Previously, the effects of espindolol on muscle mass in 19-month-old rats have been investigated, where 3 mg/kg/day espindolol treatment over a period of 4 weeks increased body weight (+8.0 ± 6.1 g, p < 0.05), particularly lean mass (+43.4 ± 3.5 g, p < 0.001), and reduced fat mass (−38.6 ± 3.4 g, p < 0.001), while placebo rats progressively lost body weight (−15.5 ± 7.2 g), lean mass (−1.5 ± 4.2 g), and fat mass (−15.6 ± 2.7 g), thereby reversing the effects of sarcopenia [112].…”