bims-aucach 2022-04-10 papers

bims-aucach

Biomed News

on Autophagy and cachexia

Issue of 2022–04–10
nine papers selected by
Kleiton Silva, Rowan University

The Mitochondria-Targeting Agent MitoQ Improves Muscle Atrophy, Weakness and Oxidative Metabolism in C26 Tumor-Bearing Mice.
Involvement of Parkin-mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease-related sarcopenia.
Sarcopenia definition: does it really matter? Implications for resistance training?
Cross Talk proposal: Myonuclei are lost with ageing and atrophy.
Anabolic-Androgenic Steroids and Exercise Training: Breaking the Myths and Dealing With Better Outcome in Sarcopenia.
Association between Sarcopenia and Insulin-Like Growth Factor-1, Myostatin, and Insulin Resistance in Elderly Patients Undergoing Hemodialysis.
The benefits of physical activity on neuromuscular structure and function in old age.
Implications of Race and Ethnicity in Sarcopenia US National Prevalence of Sarcopenia by Muscle Mass, Strength, and Function Indices.
FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice.

Front Cell Dev Biol. 2022 ;10 861622

The Mitochondria-Targeting Agent MitoQ Improves Muscle Atrophy, Weakness and Oxidative Metabolism in C26 Tumor-Bearing Mice.

Fabrizio Pin, Joshua R Huot, Andrea Bonetto.

  Cancer cachexia is a debilitating syndrome characterized by skeletal muscle wasting, weakness and fatigue. Several pathogenetic mechanisms can contribute to these muscle derangements. Mitochondrial alterations, altered metabolism and increased oxidative stress are known to promote muscle weakness and muscle catabolism. To the extent of improving cachexia, several drugs have been tested to stimulate mitochondrial function and normalize the redox balance. The aim of this study was to test the potential beneficial anti-cachectic effects of Mitoquinone Q (MitoQ), one of the most widely-used mitochondria-targeting antioxidant. Here we show that MitoQ administration (25 mg/kg in drinking water, daily) in vivo was able to improve body weight loss in Colon-26 (C26) bearers, without affecting tumor size. Consistently, the C26 hosts displayed ameliorated skeletal muscle and strength upon treatment with MitoQ. In line with improved skeletal muscle mass, the treatment with MitoQ was able to partially correct the expression of the E3 ubiquitin ligases Atrogin-1 and Murf1. Contrarily, the anabolic signaling was not improved by the treatment, as showed by unchanged AKT, mTOR and 4EBP1 phosphorylation. Assessment of gene expression showed altered levels of markers of mitochondrial biogenesis and homeostasis in the tumor hosts, although only Mitofusin-2 levels were significantly affected by the treatment. Interestingly, the levels of Pdk4 and CytB, genes involved in the regulation of mitochondrial function and metabolism, were also partially increased by MitoQ, in line with the modulation of hexokinase (HK), pyruvate dehydrogenase (PDH) and succinate dehydrogenase (SDH) enzymatic activities. The improvement of the oxidative metabolism was associated with reduced myosteatosis (i.e., intramuscular fat infiltration) in the C26 bearers receiving MitoQ, despite unchanged muscle LDL receptor expression, therefore suggesting that MitoQ could boost β-oxidation in the muscle tissue and promote a glycolytic-to-oxidative shift in muscle metabolism and fiber composition. Overall, our data identify MitoQ as an effective treatment to improve skeletal muscle mass and function in tumor hosts and further support studies aimed at testing the anti-cachectic properties of mitochondria-targeting antioxidants also in combination with routinely administered chemotherapy agents.

Keywords:  MitoQ; cachexia; cancer; metabolism; mitochondria; muscle

DOI:  https://doi.org/10.3389/fcell.2022.861622
J Cachexia Sarcopenia Muscle. 2022 Apr 03.

Involvement of Parkin-mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease-related sarcopenia.

Akihiko Ito, Mitsuo Hashimoto, Jun Tanihata, Sachi Matsubayashi, Ryoko Sasaki, Shota Fujimoto, Hironori Kawamoto, Yusuke Hosaka, Akihiro Ichikawa, Tsukasa Kadota, Yu Fujita, Daisuke Takekoshi, Sabro Ito, Shunsuke Minagawa, Takanori Numata, Hiromichi Hara, Tatsuki Matsuoka, Jun Udaka, Jun Araya, Mitsuru Saito, Kazuyoshi Kuwano.

   BACKGROUND: Sarcopenia is characterized by the loss of skeletal muscle mass and strength and is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) exposure, a major cause for COPD, induces mitochondrial damage, which has been implicated in sarcopenia pathogenesis. The current study sought to examine the involvement of insufficient Parkin-mediated mitophagy, a mitochondrion-selective autophagy, in the mechanisms by which dysfunctional mitochondria accumulate with excessive reactive oxygen species (ROS) production in the development of COPD-related sarcopenia.
METHODS: The involvement of Parkin-mediated mitophagy was examined using in vitro models of myotube formation, in vivo CS-exposure model using Parkin-/- mice, and human muscle samples from patients with COPD-related sarcopenia.
RESULTS: Cigarette smoke extract (CSE) induced myotube atrophy with concomitant 30% reduction in Parkin expression levels (P < 0.05). Parkin-mediated mitophagy regulated myotube atrophy by modulating mitochondrial damage and mitochondrial ROS production. Increased mitochondrial ROS was responsible for myotube atrophy by activating Muscle Ring Finger 1 (MuRF-1)-mediated myosin heavy chain (MHC) degradation. Parkin-/- mice with prolonged CS exposure showed enhanced limb muscle atrophy with a 31.7% reduction in limb muscle weights (P < 0.01) and 2.3 times greater MuRF-1 expression (P < 0.01) compared with wild-type mice with concomitant accumulation of damaged mitochondria and oxidative modifications in 4HNE expression. Patients with COPD-related sarcopenia exhibited significantly reduced Parkin but increased MuRF-1 protein levels (35% lower and 2.5 times greater protein levels compared with control patients, P < 0.01 and P < 0.05, respectively) and damaged mitochondria accumulation demonstrated in muscles. Electric pulse stimulation-induced muscle contraction prevented CSE-induced MHC reduction by maintaining Parkin levels in myotubes.
CONCLUSIONS: Taken together, COPD-related sarcopenia can be attributed to insufficient Parkin-mediated mitophagy and increased mitochondrial ROS causing enhanced muscle atrophy through MuRF-1 activation, which may be at least partly preventable through optimal physical exercise.

Keywords:  COPD; Cigarette smoke; Muscle atrophy; Muscle contraction; Parkin

DOI:  https://doi.org/10.1002/jcsm.12988
Ageing Res Rev. 2022 Apr 01. pii: S1568-1637(22)00059-9. [Epub ahead of print] 101617

Sarcopenia definition: does it really matter? Implications for resistance training?

Cassandra Smith, Mary N Woessner, Marc Sim, Itamar Levinger.

  The loss of muscle mass, strength and function, known as sarcopenia, is common in older adults, and is associated with falls, fractures, cardiometabolic diseases, and lower quality of life. Sarcopenia can also occur secondarily to chronic diseases. Recently, sarcopenia was recognized as a disease with an International Classification of Disease (ICD) code, yet, at least five definitions for its clinical identification exist. Most definitions include three themes: low muscle mass, strength and physical performance. However, the definitions vary by the number of themes needed to diagnose sarcopenia and, within each theme various parameters and cut-off levels exist. The lack of consensus on what constitutes a diagnosis can create confusion and hesitation in sarcopenia diagnosis. Currently, no pharmacological treatment exists for sarcopenia. Resistance training (RT) is safe and effective to improve muscle mass, strength and physical performance in older adults and clinical populations. Based on current guidelines, whether an individual is defined as "sarcopenic", or not, does not change the way RT is prescribed. Here, we present evidence and the inconsistencies in sarcopenia definitions and recommend that focus should be on optimizing ways to prescribe RT and increase long-term adherence, rather than on slight modifications to sarcopenia definitions.

Keywords:  Sarcopenia; ageing; clinical populations; exercise; older adults

DOI:  https://doi.org/10.1016/j.arr.2022.101617
J Physiol. 2022 Apr 07.

Cross Talk proposal: Myonuclei are lost with ageing and atrophy.

Tyler J Kirby, Esther E Dupont-Versteegden.



Keywords:  ageing; apoptosis; myonuclei; skeletal muscle

DOI:  https://doi.org/10.1113/JP282380
Front Physiol. 2022 ;13 838526

Anabolic-Androgenic Steroids and Exercise Training: Breaking the Myths and Dealing With Better Outcome in Sarcopenia.

Hugo Falqueto, Marcelo Rodrigues Dos Santos, Leandro H Manfredi.

  Sarcopenia is an emerging clinical condition determined by the reduction in physical function and muscle mass, being a health concern since it impairs quality of life and survival. Exercise training is a well-known approach to improve physical capacities and body composition, hence managing sarcopenia progression and worsening. However, it may be an ineffective treatment for many elderly with exercise-intolerant conditions. Thus, the use of anabolic-androgenic steroids (AAS) may be a plausible strategy, since these drugs can increase physical function and muscle mass. The decision to initiate AAS treatment should be guided by an evidence-based patient-centric perspective, once the balance between risks and benefits may change depending on the clinical condition coexisting with sarcopenia. This mini-review points out a critical appraisal of evidence and limitation of exercise training and AAS to treat sarcopenia.

Keywords:  anabolic-androgenic steroid; exercise; muscle; resistance trainig; sarcopenia

DOI:  https://doi.org/10.3389/fphys.2022.838526
J Aging Res. 2022 ;2022 1327332

Association between Sarcopenia and Insulin-Like Growth Factor-1, Myostatin, and Insulin Resistance in Elderly Patients Undergoing Hemodialysis.

Novira Widajanti, SoebagijoAdi Soelistijo, Usman Hadi, Mochammad Thaha, Aditiawardana, Widodo, Hadiq Firdausi, YafanitaIzzati Nurina, MiraDelima Asikin, Hersih Srinowati, NoerHalimatus Syakdiyah.

Sarcopenia is common in hemodialysis patients, especially in the elderly patients undergoing hemodialysis. Various factors may contribute to the occurrence of sarcopenia, such as anabolic and catabolic imbalance. This study aims to investigate the correlation of insulin-like growth factor-1 (IGF-1) levels as an anabolic factor, myostatin levels, and insulin resistance as catabolic factors with sarcopenia in the pathogenesis of sarcopenia in elderly patients undergoing hemodialysis. A total of 40 subjects aged 60 years or more who undergoing hemodialysis in Dr. Soetomo Hospital Surabaya were included in this cross-sectional study. Sarcopenia was diagnosed according to Asian Working Group Sarcopenia 2019 criteria. IGF-1, myostatin, and insulin resistance levels were measured once before hemodialysis. Subjects with sarcopenia diagnosis were 33 (82.5%), that is, 19 (47.5%) men and 14 (35%) women. There were 28 (70%) of the subjects diagnosed with severe sarcopenia. Furthermore, there were significant differences in the characteristics and geriatric parameters between the sarcopenia and nonsarcopenia groups. There were differences between the two groups in hemoglobin levels, IGF-1 levels, myostatin levels, homeostasis model assessment-insulin resistance (HOMA-IR) levels, muscle mass, handgrip strength, body mass index status, mini nutritional assessment status, and physical activity scale for elderly status (all p < 0.05). Correlation analyses showed that IGF-1 levels negatively correlated with sarcopenia status in elderly patients undergoing hemodialysis (p < 0.05). On the contrary, myostatin and HOMA-IR levels were positively correlated with sarcopenia status in elderly patients undergoing hemodialysis (all p < 0.05). Based on this recent study, IGF-1, myostatin, and insulin resistance were significantly correlated with sarcopenia in elderly patients undergoing hemodialysis.

DOI: https://doi.org/10.1155/2022/1327332
J Physiol. 2022 Apr 08.

The benefits of physical activity on neuromuscular structure and function in old age.

Steven J O'Bryan, Danielle Hiam.



Keywords:  ageing; exercise; motor unit; muscle physiology

DOI:  https://doi.org/10.1113/JP283102
Gerontol Geriatr Res. 2021 ;pii: 126. [Epub ahead of print]4(1):

Implications of Race and Ethnicity in Sarcopenia US National Prevalence of Sarcopenia by Muscle Mass, Strength, and Function Indices.

Bigman G, Ryan As.

Sarcopenia prevalence varies widely by definitions and populations, which led to the creation of new criteria by the Sarcopenia Definitions and Outcomes Consortium. Yet, the degree to which sarcopenia prevalence varies according to these criteria across race and ethnic groups in the U.S. population needs further investigation. We estimated the US national prevalence of sarcopenia using different indices among adults aged 50-80 years across race and ethnicity groups utilizing data from the National Health and Nutrition Examination Surveys (NHANES: 1999-2002 and 2011-2014). Sarcopenia was defined by appendicular lean mass divided by body mass index (ALM/BMI), grip strength, and gait speed. For each index the following samples were constructed: grip strength (NHANES 2011-2014: N=4,615), gait speed (NHANES 1999-2002: N=3,448) and ALM/BMI (NHANES 1999-2002: N=3,448) among adults aged 50-80 years. Sarcopenia prevalence varied by race/ethnicity: NH-Whites (11.2-24.3%), Hispanics (21.9-36.0%), NH-Blacks (4.4-27.7%), and Asians/others (18.5-35.7%). Based on the multivariable models, compared to NH-Whites, NH-Blacks were less likely to have sarcopenia by ALM/BMI (OR=0.26, 95%CI: 0.18-0.39), and more likely by gait speed (OR=3.90, 95% CI: 3.00-5.06) with no difference by grip strength (OR=0.96, 95%CI: 0.75-1.24). While, Hispanics and Asians/others were more likely to have sarcopenia by grip strength, gait speed, and ALM/BMI (ORs=2.15-3.21) compared to NH-Whites. This study suggests the need for inclusion of race/ethnicity related criteria in sarcopenia definitions. Future investigations could determine whether this discrepancy between race/ethnicity across sarcopenia indices, particularly in NH-Blacks, is partly due to either muscle mass or functional changes with aging.

Keywords: Appendicular lean mass; Gait speed; Grip strength; Race/Ethnicity; Sarcopenia
Nat Commun. 2022 Apr 07. 13(1): 1897

FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice.

Cristal M Hill, Diana C Albarado, Lucia G Coco, Redin A Spann, Md Shahjalal Khan, Emily Qualls-Creekmore, David H Burk, Susan J Burke, J Jason Collier, Sangho Yu, David H McDougal, Hans-Rudolf Berthoud, Heike Münzberg, Andrzej Bartke, Christopher D Morrison.

Dietary protein restriction is increasingly recognized as a unique approach to improve metabolic health, and there is increasing interest in the mechanisms underlying this beneficial effect. Recent work indicates that the hormone FGF21 mediates the metabolic effects of protein restriction in young mice. Here we demonstrate that protein restriction increases lifespan, reduces frailty, lowers body weight and adiposity, improves physical performance, improves glucose tolerance, and alters various metabolic markers within the serum, liver, and adipose tissue of wildtype male mice. Conversely, mice lacking FGF21 fail to exhibit metabolic responses to protein restriction in early life, and in later life exhibit early onset of age-related weight loss, reduced physical performance, increased frailty, and reduced lifespan. These data demonstrate that protein restriction in aging male mice exerts marked beneficial effects on lifespan and metabolic health and that a single metabolic hormone, FGF21, is essential for the anti-aging effect of this dietary intervention.

DOI: https://doi.org/10.1038/s41467-022-29499-8