Emerging Mechanisms of Skeletal Muscle Homeostasis and Cachexia: The SUMO Perspective

Abstract

Mobility is an intrinsic feature of the animal kingdom that stimulates evolutionary processes and determines the biological success of animals. Skeletal muscle is the primary driver of voluntary movements. Besides, skeletal muscles have an immense impact on regulating glucose, amino acid, and lipid homeostasis. Muscle atrophy/wasting conditions are accompanied by a drastic effect on muscle function and disrupt steady-state muscle physiology. Cachexia is a complex multifactorial muscle wasting syndrome characterized by extreme loss of skeletal muscle mass, resulting in a dramatic decrease in life quality and reported mortality in more than 30% of patients with advanced cancers. The lack of directed treatments to prevent or relieve muscle loss indicates our inadequate knowledge of molecular mechanisms involved in muscle cell organization and the molecular etiology of cancer-induced cachexia (CIC). This review highlights the latest knowledge of regulatory mechanisms involved in maintaining muscle function and their deregulation in wasting syndromes, particularly in cachexia. Recently, protein posttranslational modification by the small ubiquitin-like modifier (SUMO) has emerged as a key regulatory mechanism of protein function with implications for different aspects of cell physiology and diseases. We also review an atypical association of SUMO-mediated pathways in this context and deliberate on potential treatment strategies to alleviate muscle atrophy.

Keywords: SUMO-specific isopeptidase; cachexia; chromatin signaling; muscle atrophy; muscle metabolism; sarcomere; ubiquitin-like modifiers; ubiquitination.

Figure 1

Pathways involved in anabolic and catabolic regulation of healthy and cachectic skeletal muscle. Anabolic regulation of skeletal muscle development triggered by Insulin, IGF-1 and BCAA leads to activation of Akt and mTOR signaling to promote expression of muscle proteins and polymerization of actin filaments. CIC is promoted by the activation of E3 ubiquitin ligase MURF1 and FBXO32 transcription in IL-6-, TNFα-, Myostatin-, IFN-γ, and PIF-mediated manner. Furthermore, transcriptional activation of proteasome ATPase subunits Mss1 and p42 is NF-κB-dependent. IFN-γ signaling leads to degradation of MYOD1-transript. IL-6/STAT3/AMPK signalling deactivates mTORC1 in CIC. Chemotherapy-triggered cachexia inhibits mTOR-mediated muscle protein synthesis, and activates MuRF1 & Atrogin1-mediated degradation of sarcomeric proteins. Furthermore, chemotherapeutics like Daun inhibit myosin heavy chain expression via SENP3 degradation. Pointed arrows indicate upregulation; T shaped arrows indicate downregulation. Note that not all the known signaling pathways and interconnections among them are represented in the above schematic. ActRIIB: Activin receptor type-2B; Akt: Protein kinase B; AMPK: AMP-activated protein kinase; BCAA: Branched amino acids; CDDP: Cisplatin; C/EBPδ: CCAAT/enhancer-binding protein delta; CIC: Cancer-induced cachexia; Daun: Daunorubicin; Dox: Doxorubicin; eIF2B: Eukaryotic translation initiation factor 2 subunit 2; FBXO32: F-box only protein 32/Atrogin-1; FoxO32: Forkhead box protein O3; gp130: skeletal muscle glycoprotein 130; GSK3β: Glycogen synthase kinase-3 beta; IκBα: NFκB inhibitor α; IFNγ: Interferon gamma; IFNGR: IFNγ receptor; IGF1: Insulin-like growth factor-1; IGFR: Insulin-like growth factor-1 receptor; IL-6: Interleukin-6; IL6R: IL-6 receptor; IR: Insulin receptor; MEF2: Myocyte enhancer factor 2; mTORC1: Mammalian target of rapamycin complex 1; MuRF-1: Muscle-specific RING finger protein 1; MYH1: Myosin heavy chain 1 (IIx/d); MYH2: Myosin heavy chain 2 (IIa); MyoD1: Myoblast determination protein 1; NFκB: Nuclear factor of kappa light polypeptide gene enhancer in B-cells; NO: Nitric oxide; N-WASP: Actin nucleation-promoting factor WASL; OONO⁻: Peroxynitrite anion; P: phosphate group; PIF: Proteolysis inducing factor; PI3K: Phosphoinositide 3-kinase; PSMC2/Mss1; 26S proteasome regulatory subunit 7; PSMC6/p42: 26S proteasome regulatory subunit 10B; p70S6K: Ribosomal protein S6 kinase beta-1; ROS: Reactive oxygen species; SENP3: Sentrin-specific protease 3; SETD7: Histone-lysine N-methyltransferase SETD7; Smad2/3: Mothers against decapentaplegic homolog 2/3; STAT3: Signal transducer and activator of transcription 3; SUMO: Small ubiquitin-related modifier; Suv39h1: Histone-lysine N-methyltransferase SUV39H1; TNFα: Tumor necrosis factor alpha; TNFR: TNF receptor; ub: Ubiquitin; VP16: Etoposide; 4EBP1: Eukaryotic translation initiation factor 4E-binding protein 1; 5-FU: Fluorouracil.

Figure 2

Influence of cachexia on muscle regeneration and myogenesis. Pax7 maintains self-renewal ability of satellite cells, while TRIM32 and SUMOylation of Pax7 regulate the activation of satellite cells to form progenitor myoblast cells during muscle regeneration. Chemotherapeutics like Dox inhibit satellite cell proliferation via the mTOR pathway, thereby reducing the stem cell pool for muscle regeneration. Upon stimulation by serotonin, the JAK2-STAT3 network is activated, leading to expression of myogenin, a key determinant of myogenesis. On the other hand, IL6-led JAK1-STAT3-STAT1 activation allows downregulation of MyoD1, MEF2 and MHC, which inhibits premature myogenic differentiation and maintains sufficient number of myoblasts. The myogenic progenitor pool is additionally maintained by the expression of S-phase proteins that are regulated by SUMO-modified-G9a and PCAF complex. The surge of pro-inflammatory cytokines in cancer-induced cachexia activates NF-κB and STAT1 signaling that deregulates muscle differentiation through MyoD suppression. Additionally, CIC upregulates ZIP14 thereby leading to accumulation of zinc ion and reduced expression of key myogenic factors. Global SUMOylation is reduced during myogenesis, suggesting a strict regulation and interconnection of the various signaling networks in the process of myogenic differentiation and muscle regeneration. Pointed arrows indicate positive regulation; T shaped arrows indicate negative regulation. CIC: Cancer-induced cachexia; Dox: Doxorubicin; Erk1/2: Extracellular signal-regulated kinase 1/2; G9a: Histone-lysine N-methyltransferase EHMT2; IL-6: Interleukin 6; JAK1: Janus kinase 1; JAK2: Janus kinase 2; MHC: Myosin heavy chain; MEF2: Myocyte-specific enhancer factor 2; mTOR: Mammalian target of rapamycin; MYOD1: Myoblast determination protein 1; MYOG: Myogenin; MYF5: Myogenic factor 5; NFκB: Nuclear factor of kappa light polypeptide gene enhancer in B-cells; Pax7: Paired box protein Pax-7; PCAF: Histone acetyltransferase PCAF; STAT1: Signal transducer and activator of transcription 1; STAT3: Signal transducer and activator of transcription 3; SUMO: Small ubiquitin-related modifier; TRIM32: E3 ubiquitin-protein ligase TRIM32; ZIP14: zinc ion transporter ZRT- and IRT-like protein 14; Zn: Zinc.