scholarly journals Molecular Mechanisms, Therapeutic Targets and Pharmacological Interventions: An Update

2021 ◽  
Author(s):  
Mohit Kwatra ◽  
Sahabuddin Ahmed ◽  
Samir Ranjan Panda ◽  
Vegi Ganga Modi Naidu ◽  
Nitika Gupta
Keyword(s):  
Skeletal Muscle ◽  
Energy Expenditure ◽  
Muscle Mass ◽  
Molecular Mechanisms ◽  
Human Subjects ◽  
Therapeutic Targets ◽  
The Body ◽  
Sirtuin 1 ◽  
Pharmacological Interventions ◽  
Ubiquitin Proteasome

Muscles are the enriched reservoir of proteins in the body. During any workout or exercise, the demand in the form of energy is essentially required by the muscle. Energy expenditure of skeletal muscle is more dependent on the type of demand. There is particular homeostasis within the body that avoid surplus energy expenditure and this prevents any muscle loss. Muscle atrophy is termed as the loss of skeletal muscle mass due to immobility, malnutrition, medications, aging, cancer cachexia, variety of injuries or diseases that impact the musculoskeletal or nervous system. Hence, atrophy within the skeletal muscle initiates further cause fatigue, pain, muscle weakness, and disability in human subjects. Therefore, starvation and reduced muscle mass further initiate numerous signaling pathways including inflammatory, antioxidant signaling, mitochondria bio-energetic failure, AMP-activated protein kinase (AMPK), Sirtuin 1(SIRT1), BDNF/TrkB/PKC, Autophagy, ubiquitin-proteasome systems, etc. Here, in this chapter, we will mention molecular mechanisms involved in therapeutic targets and available Pharmacological Interventions with the latest updates.

scholarly journals p21-Activated Kinase 1 Is Permissive for the Skeletal Muscle Hypertrophy Induced by Myostatin Inhibition

2021 ◽  
Vol 12 ◽  
Author(s):  
Caroline Barbé ◽  
Audrey Loumaye ◽  
Pascale Lause ◽  
Olli Ritvos ◽  
Jean-Paul Thissen
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Muscle Hypertrophy ◽  
Molecular Mechanisms ◽  
Muscle Development ◽  
The Body ◽  
Negative Regulator ◽  
Skeletal Muscle Hypertrophy ◽  
Myostatin Inhibition

Skeletal muscle, the most abundant tissue in the body, plays vital roles in locomotion and metabolism. Understanding the cellular processes that govern regulation of muscle mass and function represents an essential step in the development of therapeutic strategies for muscular disorders. Myostatin, a member of the TGF-β family, has been identified as a negative regulator of muscle development. Indeed, its inhibition induces an extensive skeletal muscle hypertrophy requiring the activation of Smad 1/5/8 and the Insulin/IGF-I signaling pathway, but whether other molecular mechanisms are involved in this process remains to be determined. Using transcriptomic data from various Myostatin inhibition models, we identified Pak1 as a potential mediator of Myostatin action on skeletal muscle mass. Our results show that muscle PAK1 levels are systematically increased in response to Myostatin inhibition, parallel to skeletal muscle mass, regardless of the Myostatin inhibition model. Using Pak1 knockout mice, we investigated the role of Pak1 in the skeletal muscle hypertrophy induced by different approaches of Myostatin inhibition. Our findings show that Pak1 deletion does not impede the skeletal muscle hypertrophy magnitude in response to Myostatin inhibition. Therefore, Pak1 is permissive for the skeletal muscle mass increase caused by Myostatin inhibition.

scholarly journals Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 588
Author(s):  
Hayden W. Hyatt ◽  
Scott K. Powers
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Chronic Diseases ◽  
Muscle Mass ◽  
Cancer Chemotherapy ◽  
Muscle Wasting ◽  
The Body ◽  
Common Denominator ◽  
Skeletal Muscle Wasting ◽  
Vital Functions

Skeletal muscle is the most abundant tissue in the body and is required for numerous vital functions, including breathing and locomotion. Notably, deterioration of skeletal muscle mass is also highly correlated to mortality in patients suffering from chronic diseases (e.g., cancer). Numerous conditions can promote skeletal muscle wasting, including several chronic diseases, cancer chemotherapy, aging, and prolonged inactivity. Although the mechanisms responsible for this loss of muscle mass is multifactorial, mitochondrial dysfunction is predicted to be a major contributor to muscle wasting in various conditions. This systematic review will highlight the biochemical pathways that have been shown to link mitochondrial dysfunction to skeletal muscle wasting. Importantly, we will discuss the experimental evidence that connects mitochondrial dysfunction to muscle wasting in specific diseases (i.e., cancer and sepsis), aging, cancer chemotherapy, and prolonged muscle inactivity (e.g., limb immobilization). Finally, in hopes of stimulating future research, we conclude with a discussion of important future directions for research in the field of muscle wasting.

Change in skeletal muscle index and its prognostic significance in conversion therapy for initially unresectable colorectal cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 56-56
Author(s):  
Hiroaki Nozawa ◽  
Shigenobu Emoto ◽  
Koji Murono ◽  
Yasutaka Shuno ◽  
Soichiro Ishihara
Keyword(s):  
Colorectal Cancer ◽  
Skeletal Muscle ◽  
Muscle Mass ◽  
Skeletal Muscles ◽  
Systemic Chemotherapy ◽  
Stage Iv ◽  
The Body ◽  
Pharmacological Intervention ◽  
Conversion Therapy ◽  
Skeletal Muscle Index

56 Background: Systemic chemotherapy can cause loss of skeletal muscle mass in colorectal cancer (CRC) patients in the neoadjuvant and palliative settings. However, it is largely unknown how the body composition is changed by chemotherapy rendering unresectable CRC to resectable disease or how it affects the prognosis. This study aimed at elucidating the effects of systemic chemotherapy on skeletal muscles and survival in stage IV CRC patients who underwent conversion therapy. Methods: We reviewed 98 stage IV CRC patients who received systemic chemotherapy in our hospital. According to the treatment setting, patients were divided into the ‘Conversion’, ‘Neoadjuvant chemotherapy (NAC)’, and ‘Palliation’ groups. The cross-sectional area of skeletal muscles at the third lumbar level and changes in the skeletal muscle index (SMI), defined as the area divided by height squared, during chemotherapy were compared among patient groups. The effects of these parameters on prognosis were analyzed in the Conversion group. Results: The mean SMI increased by 8.0% during chemotherapy in the Conversion group (n = 38), whereas it decreased by 6.2% in the NAC group (n = 18) and 3.7% in the Palliation group (n = 42, p < 0.0001). Moreover, patients with increased SMI during chemotherapy had a better overall survival (OS) than those whose SMI decreased in the Conversion group (p = 0.021). The increase in SMI was an independent predictor of favorable OS on multivariate analysis (hazard ratio: 0.26). Conclusions: Stage IV CRC patients who underwent conversion to resection often had an increased SMI. As such an increase in SMI further conveys a survival benefit in conversion therapy, it may be important to make efforts to preserve muscle mass by meticulous approaches, such as nutritional support, muscle exercise programs, and pharmacological intervention even during chemotherapy in patients with metastatic CRC.

scholarly journals Exercise Mitigates the Loss of Muscle Mass by Attenuating the Activation of Autophagy during Severe Energy Deficit

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2824 ◽  
Author(s):  
Marcos Martin-Rincon ◽  
Alberto Pérez-López ◽  
David Morales-Alamo ◽  
Ismael Perez-Suarez ◽  
Pedro de Pablos-Velasco ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Prolonged Exercise ◽  
Control Diet ◽  
Energy Deficit ◽  
Muscle Loss ◽  
Volume Changes ◽  
Autophagy Induction ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The loss of skeletal muscle mass with energy deficit is thought to be due to protein breakdown by the autophagy-lysosome and the ubiquitin-proteasome systems. We studied the main signaling pathways through which exercise can attenuate the loss of muscle mass during severe energy deficit (5500 kcal/day). Overweight men followed four days of caloric restriction (3.2 kcal/kg body weight day) and prolonged exercise (45 min of one-arm cranking and 8 h walking/day), and three days of control diet and restricted exercise, with an intra-subject design including biopsies from muscles submitted to distinct exercise volumes. Gene expression and signaling data indicate that the main catabolic pathway activated during severe energy deficit in skeletal muscle is the autophagy-lysosome pathway, without apparent activation of the ubiquitin-proteasome pathway. Markers of autophagy induction and flux were reduced by exercise primarily in the muscle submitted to an exceptional exercise volume. Changes in signaling are associated with those in circulating cortisol, testosterone, cortisol/testosterone ratio, insulin, BCAA, and leucine. We conclude that exercise mitigates the loss of muscle mass by attenuating autophagy activation, blunting the phosphorylation of AMPK/ULK1/Beclin1, and leading to p62/SQSTM1 accumulation. This includes the possibility of inhibiting autophagy as a mechanism to counteract muscle loss in humans under severe energy deficit.

scholarly journals Arrdc2 and Arrdc3 elicit divergent changes in gene expression in skeletal muscle following anabolic and catabolic stimuli

2019 ◽  
Vol 51 (6) ◽  
pp. 208-217 ◽  
Author(s):  
Bradley S. Gordon ◽  
Michael L. Rossetti ◽  
Alexey M. Eroshkin
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Tibialis Anterior ◽  
Gene Networks ◽  
Tibialis Anterior Muscle ◽  
The Body ◽  
Molecular Networks ◽  
Expression Of Genes ◽  
Consistent Change ◽  
Mechanical Overload

Skeletal muscle is a highly plastic organ regulating various processes in the body. As such, loss of skeletal muscle underlies the increased morbidity and mortality risk that is associated with numerous conditions. However, no therapies are available to combat the loss of muscle mass during atrophic conditions, which is due in part to the incomplete understanding of the molecular networks altered by anabolic and catabolic stimuli. Thus, the current objective was to identify novel gene networks modulated by such stimuli. For this, total RNA from the tibialis anterior muscle of mice that were fasted overnight or fasted overnight and refed the next morning was subjected to microarray analysis. The refeeding stimulus altered the expression of genes associated with signal transduction. Specifically, expression of alpha arrestin domain containing 2 (Arrdc2) and alpha arrestin domain containing 3 (Arrdc3) was significantly lowered 70–85% by refeeding. Subsequent analysis showed that expression of these genes was also lowered 50–75% by mechanical overload, with the combination of nutrients and mechanical overload acting synergistically to lower Arrdc2 and Arrdc3 expression. On the converse, stimuli that suppress growth such as testosterone depletion or acute aerobic exercise increased Arrdc2 and Arrdc3 expression in skeletal muscle. While Arrdc2 and Arrdc3 exhibited divergent changes in expression following anabolic or catabolic stimuli, no other member of the Arrdc family of genes exhibited the consistent change in expression across the analyzed conditions. Thus, Arrdc2 and Arrdc3 are a novel set of genes that may be implicated in the regulation of skeletal muscle mass.

scholarly journals The Association between Serum Uric Acid and Appendicular Skeletal Muscle Mass and the Effect of Their Interaction on Mortality in Patients on Peritoneal Dialysis

2020 ◽  
Vol 45 (6) ◽  
pp. 969-981
Author(s):  
Xi Xiao ◽  
Chunyan Yi ◽  
Yuan Peng ◽  
Hongjian Ye ◽  
Haishan Wu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Uric Acid ◽  
Peritoneal Dialysis ◽  
Serum Uric Acid ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
The Body ◽  
All Cause Mortality ◽  
Appendicular Skeletal Muscle ◽  
Appendicular Skeletal Muscle Mass

<b><i>Background:</i></b> Serum uric acid (SUA) has been revealed to be positively associated with the body composition parameters in hemodialysis patients, but few studies have investigated that in patients on peritoneal dialysis (PD). The aim of this study was to identify the relationship between SUA and appendicular skeletal muscle mass (ASM) and the effect of their interaction on mortality in PD patients. <b><i>Methods:</i></b> This was a single-center retrospective cohort study. Patients who underwent multifrequency bioelectrical impedance analysis between January 1, 2013, and December 31, 2016, and had data on SUA values were enrolled. All patients were followed up until December 31, 2019. <b><i>Results:</i></b> In total, 802 prevalent PD patients (57.9% male), with mean age of 46.2 ± 14.2 years were enrolled. The average SUA and ASM were 6.8 ± 1.3 mg/dL and 21.2 ± 4.9 kg. According to multiple linear regression models, SUA was positively associated with relative ASM in middle-aged and older PD patients (standardized coefficients [β] 0.117; 95% confidence interval [CI] 0.027, 0.200; <i>p</i> = 0.010). Further sex-stratified analysis showed that the association existed only in males (β 0.161; 95% CI 0.017, 0.227; <i>p</i> = 0.023). Moreover, the presence of hyperuricemia was found to predict lower risk of all-cause mortality (hazard ratio [HR] 0.514, 95% CI 0.272, 0.970; <i>p</i> = 0.040) only in patients with lower relative ASM. And, the adjusted HR of every 1 mg/dL elevated SUA level was 0.770 (95% CI 0.609, 0.972; <i>p</i> = 0.028) for all-cause mortality in the lower relative ASM subgroup. <b><i>Conclusions:</i></b> There exists a positive association between the SUA and ASM, and the ASM significantly affected the association between SUA and all-cause PD mortality.

scholarly journals MuRF1/TRIM63, Master Regulator of Muscle Mass

2020 ◽  
Vol 21 (18) ◽  
pp. 6663 ◽  
Author(s):  
Dulce Peris-Moreno ◽  
Daniel Taillandier ◽  
Cécile Polge
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Skeletal Muscle Atrophy ◽  
Cardiac Functions ◽  
Important Player ◽  
Cardiac Muscles ◽  
Inhibitory Molecules

The E3 ubiquitin ligase MuRF1/TRIM63 was identified 20 years ago and suspected to play important roles during skeletal muscle atrophy. Since then, numerous studies have been conducted to decipher the roles, molecular mechanisms and regulation of this enzyme. This revealed that MuRF1 is an important player in the skeletal muscle atrophy process occurring during catabolic states, making MuRF1 a prime candidate for pharmacological treatments against muscle wasting. Indeed, muscle wasting is an associated event of several diseases (e.g., cancer, sepsis, diabetes, renal failure, etc.) and negatively impacts the prognosis of patients, which has stimulated the search for MuRF1 inhibitory molecules. However, studies on MuRF1 cardiac functions revealed that MuRF1 is also cardioprotective, revealing a yin and yang role of MuRF1, being detrimental in skeletal muscle and beneficial in the heart. This review discusses data obtained on MuRF1, both in skeletal and cardiac muscles, over the past 20 years, regarding the structure, the regulation, the location and the different functions identified, and the first inhibitors reported, and aim to draw the picture of what is known about MuRF1. The review also discusses important MuRF1 characteristics to consider for the design of future drugs to maintain skeletal muscle mass in patients with different pathologies.

scholarly journals CLOCK and BMAL1 Regulate Muscle Insulin Sensitivity via SIRT1 in Male Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (6) ◽  
pp. 2259-2269 ◽  
Author(s):  
Jun Liu ◽  
Ben Zhou ◽  
Menghong Yan ◽  
Rui Huang ◽  
Yuangao Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Sirtuin 1 ◽  
C2c12 Myotubes ◽  
Constant Darkness ◽  
Circadian Misalignment ◽  
Mouse Skeletal Muscle

Circadian misalignment induces insulin resistance in both human and animal models, and skeletal muscle is the largest organ response to insulin. However, how circadian clock regulates muscle insulin sensitivity and the underlying molecular mechanisms are still largely unknown. Here we show circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1, two core circadian transcription factors, are down-regulated in insulin-resistant C2C12 myotubes and mouse skeletal muscle. Furthermore, insulin signaling is attenuated in the skeletal muscle of ClockΔ19/Δ19 mice, and knockdown of CLOCK or BMAL1 by small interfering RNAs induces insulin resistance in C2C12 myotubes. Consistently, ectopic expression of CLOCK and BMAL1 improves insulin sensitivity in C2C12 myotubes. Moreover, CLOCK and BMAL1 regulate the expression of sirtuin 1 (SIRT1), an important regulator of insulin sensitivity, in C2C12 myotubes and mouse skeletal muscle, and two E-box elements in Sirt1 promoter are responsible for its CLOCK- and BMAL1-dependent transcription in muscle cells. Further studies show that CLOCK and BMAL1 regulate muscle insulin sensitivity through SIRT1. In addition, we find that BMAL1 and SIRT1 are decreased in the muscle of mice maintained in constant darkness, and resveratrol supplementation activates SIRT1 and improves insulin sensitivity. All these data demonstrate that CLOCK and BMAL1 regulate muscle insulin sensitivity via SIRT1, and activation of SIRT1 might be a potential valuable strategy to attenuate muscle insulin resistance related to circadian misalignment.

Effects of experimental weight perturbation on skeletal muscle work efficiency in human subjects

2003 ◽  
Vol 285 (1) ◽  
pp. R183-R192 ◽  
Author(s):  
Michael Rosenbaum ◽  
Krista Vandenborne ◽  
Rochelle Goldsmith ◽  
Jean-Aime Simoneau ◽  
Steven Heymsfield ◽  
...  
Keyword(s):  
Physical Activity ◽  
Skeletal Muscle ◽  
Body Weight ◽  
Energy Expenditure ◽  
Human Subjects ◽  
Cycle Ergometry ◽  
Resonance Spectroscopy ◽  
Work Efficiency ◽  
Initial Weight ◽  
Muscle Work

Maintenance of reduced or elevated body weight results in respective decreases or increases in energy expended in physical activity, defined as 24-h energy expenditure excluding resting energy expenditure and the thermic effect of feeding, beyond those attributable to weight change. We examined skeletal muscle work efficiency by graded cycle ergometry and, in some subjects, rates of gastrocnemius muscle ATP flux during exercise by magnetic resonance spectroscopy (MRS), in 30 subjects (15 males, 15 females) at initial weight and 10% below initial weight and in 8 subjects (7 males, 1 female) at initial weight and 10% above initial weight to determine whether changes in skeletal muscle work efficiency at altered body weight were correlated with changes in the energy expended in physical activity. At reduced weight, muscle work efficiency was increased in both cycle ergometry [mean (SD) change = +26.5 (26.7)%, P < 0.001] and MRS [ATP flux change = -15.2 (23.2)%, P = 0.044] studies. Weight gain resulted in decreased muscle work efficiency by ergometry [mean (SD) change = -17.8 (20.5)%, P = 0.043]. Changes in muscle efficiency at altered body weight accounted for 35% of the change in daily energy expended in physical activity.

Sign in / Sign up

Export Citation Format

Share Document