Emerging Strategies Targeting Catabolic Muscle Stress Relief

Abstract

<jats:p>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.</jats:p>

Skeletal muscle atrophy in heart failure with diabetes: from molecular mechanisms to clinical evidence

“…The molecular signalling pathways that interact to control protein synthesis/degradation generally include the insulin-like growth factor 1 (IGF1)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)-forkhead box protein O (FoxO), TGF-β/myostatin/bone morphogenetic protein (BMP), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and glucocorticoid 58 ( Figure 2), which are flexible to modulation. 3 These signalling pathways regulate the fate of many proteins, which include degradation by one of the four major proteolytic systems in the cell: ubiquitin-proteasome, autophagy-lysosome, calpain, and caspase. 58 Typically, in atrophic conditions, evidence exists to support that proteolysis is elevated while protein synthesis is blunted; however, there is ongoing debate as to whether elevated proteolysis or supressed protein synthesis is the primary mechanism responsible for atrophy in catabolic conditions, which seems to be highly dependent on the clinical condition and experimental model employed.…”

“…Wasting of skeletal muscle, referred to as atrophy, is characteristic of several catabolic conditions, including aging (i.e. sarcopenia), starvation, and immobilization, but also occurs as a consequence of chronic disease 2,3 . Cachexia is closely linked to muscle atrophy and is defined as a complex multifactorial metabolic syndrome, which is associated with a significant reduction in body mass underpinned by skeletal muscle loss (with or without fat mass loss) and not fully reversible with nutritional aids 4 .…”

“…sarcopenia), starvation, and immobilization, but also occurs as a consequence of chronic disease. 2,3 Cachexia is closely linked to muscle atrophy and is defined as a complex multifactorial metabolic syndrome, which is associated with a significant reduction in body mass underpinned by skeletal muscle loss (with or without fat mass loss) and not fully reversible with nutritional aids. 4 On the other hand, sarcopenia is the slow and progressive loss of muscle mass without any underlying disease, associated with advanced age.…”

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

“…Activation of the UPS is induced in stressed muscles by specific atrogenes that function as ubiquitin E3 ligases to multiubiquitinate muscle proteins, thereby subjecting them to proteasome-dependent degradation [ 8 , 9 , 10 ]. So far, two ubiquitin ligases, MAFBx (“muscle atrophy F-box protein”, also called atrogin-1) and MuRF1 (“muscle-specific RING finger protein-1”), and their relationship with muscle diseases, have been characterized in the most detail (for review, [ 11 , 12 ]). Both MAFBx and MuRF1 transcripts are markedly upregulated during muscle wasting states, thereby coupling enhanced muscle catabolism to UPS activation and promoting atrophy development by the downregulation of the IGF-1/Akt/mTOR pathway [ 13 , 14 , 15 , 16 ].…”

UBE2L3, a Partner of MuRF1/TRIM63, Is Involved in the Degradation of Myofibrillar Actin and Myosin

“…Inhibiting muscle atrophy has been shown to extend the life span of tumor bearing animals [52]. Developing such strategies has thus raised the interest of several laboratories for targeting different actors of muscle atrophy (for reviews, see References [13,53]).…”