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

Abstract

Patients with malignant tumors frequently suffer during disease progression from a syndrome referred to as cancer cachexia (CaCax): CaCax includes skeletal muscle atrophy and weakness, loss of bodyweight, and fat tissues. Currently, there are no FDA (Food and Drug Administration) approved treatments available for CaCax. Here, we studied skeletal muscle atrophy and dysfunction in a murine CaCax model by injecting B16F10 melanoma cells into mouse thighs and followed mice during melanoma outgrowth. Skeletal muscles developed progressive weakness as detected by wire hang tests (WHTs) during days 13–23. Individual muscles analyzed at day 24 had atrophy, mitochondrial dysfunction, augmented metabolic reactive oxygen species (ROS) stress, and a catabolically activated ubiquitin proteasome system (UPS), including upregulated MuRF1. Accordingly, we tested as an experimental intervention of recently identified small molecules, Myomed-205 and -946, that inhibit MuRF1 activity and MuRF1/MuRF2 expression. Results indicate that MuRF1 inhibitor fed attenuated induction of MuRF1 in tumor stressed muscles. In addition, the compounds augmented muscle performance in WHTs and attenuated muscle weight loss. Myomed-205 and -946 also rescued citrate synthase and complex-1 activities in tumor-stressed muscles, possibly suggesting that mitochondrial-metabolic and muscle wasting effects in this CaCax model are mechanistically connected. Inhibition of MuRF1 during tumor cachexia may represent a suitable strategy to attenuate skeletal muscle atrophy and dysfunction.

Regulation of Glucose Metabolism by MuRF1 and Treatment of Myopathy in Diabetic Mice with Small Molecules Targeting MuRF1

“…Next, we studied the effects of the recently described small molecules that inhibit MuRF1 [ 19 , 20 , 21 ] in a mouse model for T2DM. We hypothesized that such a treatment might attenuate the myopathy accompanying T2DM by inhibiting the MuRF1 atrogene functions.…”

“…Accordingly, the inhibition of cachexia promoting E3 ligases could be a potential treatment strategy to attenuate secondary myopathies. In line with this rationale, we recently identified MuRF1 inhibiting small molecules that slow down muscle mass and force loss in cardiac and cancer cachexia, respectively [ 19 , 20 , 21 ]. Here, we investigated if two compounds from this novel class of (2-oxo-chromen-7-yl)-heteromethyl-benzoic acids; i.e., MyoMed-205 and MyoMed-946 [ 21 ]) also have the potential to attenuate a secondary myopathy in a type 2 diabetes mellitus (T2DM) murine model.…”

“…In line with this rationale, we recently identified MuRF1 inhibiting small molecules that slow down muscle mass and force loss in cardiac and cancer cachexia, respectively [ 19 , 20 , 21 ]. Here, we investigated if two compounds from this novel class of (2-oxo-chromen-7-yl)-heteromethyl-benzoic acids; i.e., MyoMed-205 and MyoMed-946 [ 21 ]) also have the potential to attenuate a secondary myopathy in a type 2 diabetes mellitus (T2DM) murine model. Since a previous study with MuRF1 overexpressing transgenic mice (“MuRF1 transgenes” or brief MuRF1-Tg) implicated MuRF1 also in glucose–insulin regulation [ 22 ], we first studied the effects of MuRF1 gene inactivation on glucose metabolism in mice.…”

Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control

“…This compound was at least partially effective for preserving muscle mass in catabolic mice. The mechanism by which compound ID#704946/MyoMed-946 preserve muscle function needs further investigations as the same laboratory found that it was also able to modulate MuRF2 expression [ 17 , 18 ].…”

“…Within muscle atrophy, numerous ubiquitinating enzymes are now identified for their involvement in the regulation of both anabolic and catabolic pathways during the atrophy process, notably by being responsible for the degradation of the contractile proteins [ 12 ]. The E3 Ub ligases appear to be at the heart of these regulations and some of them may prove to be efficient therapeutic drug strategies with roughly two main approaches: (i) indirect modulation of an E3 ligase by targeting the signals involved in its regulation [ 13 , 14 , 15 , 16 ] or (ii) direct inhibition of the E3 ligase [ 17 , 18 , 19 ]. However, the intertwinement between anabolic and catabolic processes (including the signaling pathways) often renders difficult an indirect modulation of E3 ligases, while direct inhibition strategies is limited by the somehow limited data available on E3 ligases.…”