Abstract
Skeletal muscle wasting represents a common trait in many conditions, including aging, cancer, heart failure, immobilization, and critical illness. Loss of muscle mass leads to impaired functional mobility and severely impedes the quality of life. At present, exercise training remains the only proven treatment for muscle atrophy, yet many patients are too ill, frail, bedridden, or neurologically impaired to perform physical exertion. The development of novel therapeutic strategies that can be applied to an in vivo context and attenuate secondary myopathies represents an unmet medical need. This review discusses recent progress in understanding the molecular pathways involved in regulating skeletal muscle wasting with a focus on pro-catabolic factors, in particular, the ubiquitin-proteasome system and its activating muscle-specific E3 ligase RING-finger protein 1 (MuRF1). Mechanistic progress has provided the opportunity to design experimental therapeutic concepts that may affect the ubiquitin-proteasome system and prevent subsequent muscle wasting, with novel advances made in regards to nutritional supplements, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) inhibitors, myostatin antibodies, β2 adrenergic agonists, and small-molecules interfering with MuRF1, which all emerge as a novel in vivo treatment strategies for muscle wasting.
Highlights
Skeletal muscle is the largest and one of the most dynamic organs in the human body, representing 30–40% of total body mass and containing up to 75% of the organism’s protein reserves [1]
Consistent with this, we have found treatment with this small molecule can partially rescue muscle mitochondrial morphology and function [82], which are possibly in line with earlier yeast two-hybrid studies that showed that muscle-specific E3 ligase RING-finger protein 1 (MuRF1) can preferentially target mitochondrial in addition to sarcomeric proteins [115], and implicate possible localization within mitochondria as recently reported in cardiac muscle [116]
Other groups have focused on small-molecule therapeutics using non-biased approaches without any predefined targets based upon mRNA signatures in atrophy [126]. These studies have resulted in anabolic signaling pathways being primarily modulated as a mean to inhibit subsequent proteolysis, with ursolic acid and tomatidine identified as novel small-molecules that suppress MuRF1 expression and muscle wasting in aging, starvation and disuse atrophy, by blocking expression of activating transcription factor 4 (ATF4)-Gadd45a/MEKK4 kinase complex activation [126]
Summary
Skeletal muscle is the largest and one of the most dynamic organs in the human body, representing 30–40% of total body mass and containing up to 75% of the organism’s protein reserves [1]. Our current lack of direct treatments to rescue muscle wasting across millions of patients is a key concern, with exercise training the only established intervention [5]. Given that many patients are too ill or bedridden to perform exertional exercise, the development of novel pharmacological strategies to inhibit muscle atrophy represents an important research avenue. In this context, targeted inhibition of procatabolic factors activated under wasting conditions could offer the most beneficial treatment strategy for patients [6,7,8]. The current review, will address novel approaches that may permit modulation of procatabolic factors upregulated across various wasting conditions that impact muscle homeostasis. We discuss recent advances in pharmacological aids that have shown potential in vivo application for inhibiting both upstream and downstream control nodes in this system and limit muscle wasting across various catabolic conditions
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