Commentary for “antagonizing urotensin receptor is a novel therapeutic strategy for glucocorticoid‐induced skeletal muscle atrophy”

Abstract

In 1950, the discovery of the glucocorticoid cortisone was awarded the Nobel Prize in Physiology and Medicine. Since then, glucocorticoids have been a mainstay in clinical practice. Endogenous glucocorticoids like cortisone are natural hormones released in response to stress or circadian stimuli, whereas synthetic glucocorticoids like dexamethasone are used as potent anti-inflammatory drugs. While synthetic glucocorticoids are the mainstay treatments for many clinical conditions, their chronic daily intake also induces a plethora of concerning adverse effects, including muscle loss. The debilitating effects of chronic daily glucocorticoids in muscle are generally evident quite rapidly and compromise muscle mass, structure and strength in the long term. Glucocorticoid-induced muscle wasting correlates with increased protein catabolism, muscle mass decrease and inhibition of endogenous regenerative potential.1, 2 The neuropeptide urotensin II (UII) and its receptor, UII receptor, are expressed in a variety of tissues, including the skeletal muscle. Impaired regulation of UII and UII receptor have been associated with various pathologies.3 Of relevance for this study, prior studies had reported on the correlation between UII and muscle atrophy and on the finding that UII promotes loss of muscle weight and strength.4 In the study published here, Yin et al., show a novel approach in which a UII receptor antagonist rescues the glucocorticoid-induced skeletal muscle atrophy in mice. The study reports a potentially clinically relevant effect of Palosuran, a potent and selective antagonist of the UII receptor, in preventing dexamethasone-induced muscle atrophy. This experimental study has a huge potential and, if confirmed in clinical studies, could alleviate the muscle wasting experienced by the many people who take glucocorticoids regularly. Though this is the first report using this drug to counteract muscle atrophy, Palosuran has been largely investigated in the context of kidney function, particularly diabetic nephropathy. Experimental studies in rodents have reported on the potential role of UII receptor antagonists in alleviating renal complications in diabetes.5 However, initial clinical studies in humans have provided mixed results with this drug in the treatment of diabetic nephropathy.6, 7 In the study presented here, the Authors investigate a novel context for this drug and detail a large set of compelling experiments to elucidate the muscle atrophy counteraction by Palosuran. Importantly, their pharmacological experiments were complemented by analyses in a transgenic mouse with body-wide germline knockout of the UII receptor gene. Taken together, the findings reported in this study show that UII antagonism improves muscle mass and function in the context of dexamethasone-induced muscle wasting. Several limitations and open questions need further discussion. While inhibition of the UII axis through UII receptor antagonists has shown promising results in experimental animals, a potent and safe antagonist that can be used in humans is yet to be found. While the results by Yin et al, are promising, additional mechanistic and clinical studies are needed to support the novel indication of Palosuran for glucocorticoid-induced muscle loss. For instance, the experiments presented here should be investigated in disease models where chronic glucocorticoid intake is the mainstay treatment. Moreover, many tissues in the body express the UII receptor and therefore a thorough evaluation of toxicity and off-target effects of UII antagonist regimens is warranted. Additionally, it should also be evaluated if Palosuran alters or interacts with the anti-inflammatory action of glucocorticoid drugs. The results presented in this study depict a rather convincing effect of Palosuran on counteracting the loss of muscle mass and strength. However, the study did not address the effects of UII signalling and its counteraction on individual myofiber types, particularly type 2A, 2B and 2X. Moreover, the effects of UII axis activation versus inhibition on muscle bioenergetics remain unknown. Nevertheless, the rich dataset presented in this study supports the novel idea of repurposing UII antagonists to treat or prevent glucocorticoid-induced muscle atrophy. This is a significant advancement not only to potentially reduce the iatrogenic burden of synthetic glucocorticoids but also to further decipher their multifaceted action in health and disease. Drs. Prabakaran, Panta and Quattrocelli contributed to the preparation and collection of original literatures and figures and the writing and editing of manuscript. Drs. Prabakaran, Panta and Quattrocelli were responsible for the structural designs, scientific quality and writing. Not applicable. This work was supported by the following grant support: NIH grants DK121875 (MQ), HL158531 (MQ); CCHMC grants Trustee Award (MQ), Heart Institute Translational Grant (MQ). The authors declare no conflict of interest. The paper was handled by editors and has undergone a rigorous peer-review process. Dr. Mattia Quattrocelli was not involved in the journal's review of/or decisions related to this manuscript. Not applicable. Data sharing is not applicable to this article as no new data were created or analyzed in this study.