Inhibition of Stat3 signaling ameliorates atrophy of the soleus muscles in mice lacking the vitamin D receptor

Abstract

BackgroundAlthough skeletal muscle wasting has long been observed as a clinical outcome of impaired vitamin D signaling, precise molecular mechanisms that mediate the loss of muscle mass in the absence of vitamin D signaling are less clear. To determine the molecular consequences of vitamin D signaling, we analyzed the role of signal transducer and activator of transcription 3 (Stat3) signaling, a known contributor to various muscle wasting pathologies, in skeletal muscles.MethodsWe isolated soleus (slow) and tibialis anterior (fast) muscles from mice lacking the vitamin D receptor (VDR−/−) and used western blot analysis, quantitative RTPCR, and pharmacological intervention to analyze muscle atrophy in VDR−/− mice.ResultsWe found that slow and fast subsets of muscles of the VDR−/− mice displayed elevated levels of phosphorylated Stat3 accompanied by an increase in Myostatin expression and signaling. Consequently, we observed reduced activity of mammalian target of rapamycin (mTOR) signaling components, ribosomal S6 kinase (p70S6K) and ribosomal S6 protein (rpS6), that regulate protein synthesis and cell size, respectively. Concomitantly, we observed an increase in atrophy regulators and a block in autophagic gene expression. An examination of the upstream regulation of Stat3 levels in VDR−/− muscles revealed an increase in IL-6 protein expression in the soleus, but not in the tibialis anterior muscles. To investigate the involvement of satellite cells (SCs) in atrophy in VDR−/− mice, we found that there was no significant deficit in SC numbers in VDR−/− muscles compared to the wild type. Unlike its expression within VDR−/− fibers, Myostatin levels in VDR−/− SCs from bulk muscles were similar to those of wild type. However, VDR−/− SCs induced to differentiate in culture displayed increased p-Stat3 signaling and Myostatin expression. Finally, VDR−/− mice injected with a Stat3 inhibitor displayed reduced Myostatin expression and function and restored active p70S6K and rpS6 levels, resulting in an amelioration of loss of muscle mass in the soleus muscles.ConclusionsThe loss of muscle mass in slow muscles in the absence of vitamin D signaling is due to elevated levels of phosphorylated Stat3 that leads to an increase in Myostatin signaling, which in turn decreases protein synthesis and fiber size through the phosphorylation of p70S6K and rpS6, respectively.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-017-0121-2) contains supplementary material, which is available to authorized users.

Oxaliplatin induces muscle loss and muscle‐specific molecular changes in Mice

“…39 However, there is a significant minority of patients in whom the fatigue is persistent and disabling, for months or years after likely curative cancer treatment. 44,48,49 The symptom complex of this posttreatment fatigue is very similar to that of chronic fatigue syndrome, including the characteristic fatigue, neurocognitive difficulties, disturbances in sleep-wake cycle and mood, and reduced physical function. 39 Given that the impact of posttreatment fatigue in the adjuvant setting is a key issue affecting cancer survivors, our work has implications for examining the role of interventions, such as graduated exercise [50][51][52] and pharmacological interventions.…”

“…Increased STAT3 tyrosine phosphorylation (tyrosine 705) is a pertinent indicator of canonical STAT3 protein activation, and is representative of an initial upstream inflammatory mediator of muscle wasting . Importantly, STAT3 is a major contributor to muscle atrophy in cancer cachexia and various other muscle pathologies, with blockade of STAT3 signaling leading to amelioration of muscle loss . Alternatively, some studies have demonstrated that oxaliplatin downregulates STAT3 phosphorylation (Tyr705) and activation in cancer cells .…”

“…Fatigue is a common side effect of cancer and chemotherapy, affecting patients before, during, and after treatment . However, there is a significant minority of patients in whom the fatigue is persistent and disabling, for months or years after likely curative cancer treatment . The symptom complex of this posttreatment fatigue is very similar to that of chronic fatigue syndrome, including the characteristic fatigue, neurocognitive difficulties, disturbances in sleep–wake cycle and mood, and reduced physical function .…”

“…15 Importantly, STAT3 is a major contributor to muscle atrophy in cancer cachexia and various other muscle pathologies, with blockade of STAT3 signaling leading to amelioration of muscle loss. 15,44 Alternatively, some studies have demonstrated that oxaliplatin downregulates STAT3 phosphorylation (Tyr705) and activation in cancer cells. 45,46 Our results therefore suggest novel systemic effects in skeletal muscle and a tissue-specific molecular response to oxaliplatin.…”

Muscle‐specific differences in expression and phosphorylation of the Janus kinase 2/Signal Transducer and Activator of Transcription 3 following long‐term mechanical ventilation and immobilization in rats

“…Activation of STAT3 signalling through IL-6 binding to IL-6 receptors has been linked to muscle wasting via stimulation of the myostatin pathway. 33 However, our analyses showed that myostatin (Mstn) gene expression and the activin IIb receptor (Acvr2b) were not affected in response to both short-and long-term exposure to the ICU condition in all investigated muscles ( Figure 5A,B). In addition, ALK4 (Acvr1b) expression was not changed in response to short-and long-term exposure to the ICU condition, except for short-term exposure in the diaphragm where the ALK4 level was induced (P < .05; Figure 5A).…”