Article first published online:  30 January 2020

Jean‐Christophe Lagacé, Martin Brochu, Isabelle J. Dionne

A counterintuitive perspective for the role of fat‐free mass in metabolic health
Fat‐free mass (FFM) has long been recognized to play a role in metabolic homeostasis. Over the years, it has become widely accepted by the scientific and general community alike that having a greater FFM can be protective for metabolic health. Hence, in the context of an aging population concurrently facing sarcopenia and an elevated incidence of metabolic diseases, substantial efforts are being made to study and develop interventions aiming to maintain or increase FFM. However, accumulating evidence now suggests that a large FFM may be deleterious to metabolic health, at least in some populations. The objective of this article is thus to raise awareness surrounding these results and to explore possible explanations and mechanisms underlying this counterintuitive association.

Lagacé, J.‐C., Brochu, M., and Dionne, I. J. ( 2020) A counterintuitive perspective for the role of fat‐free mass in metabolic health, Journal of Cachexia, Sarcopenia and Muscle, 11, 343– 347. https://doi.org/10.1002/jcsm.12520.

ABSTRACT | PDF |

 

     Article first published online:  27 January 2020

Shuang Rong, Liangliang Wang, Zhao Peng, Yuxiao Liao, Dan Li, Xuefeng Yang, Andreas K. Nuessler, Liegang Liu, Wei Bao, Wei Yang

The mechanisms and treatments for sarcopenia: could exosomes be a perspective research strategy in the future?
The age‐related loss of muscle mass and muscle function known as sarcopenia is a primary contributor to the problems faced by the old people. Sarcopenia has been a major public health problem with high prevalence in many countries. The related underlying molecular mechanisms of sarcopenia are not completely understood. This review is focused on the potential mechanisms and current research strategies for sarcopenia with the aim of facilitating the recognition and treatment of age‐related sarcopenia. Previous studies suggested that protein synthesis and degradation, autophagy, impaired satellite cell activation, mitochondria dysfunction, and other factors associated with muscle weakness and muscle degeneration may be potential molecular pathophysiology of sarcopenia. Importantly, we also prospectively highlight that exosomes (small vesicles) as carriers can regulate muscle regeneration and protein synthesis according to recent researches. Dietary strategies and exercise represent the interventions that can also alleviate the progression of sarcopenia. At last, building on recent studies pointing to exosomes with the roles in increasing muscle regeneration, mediating the beneficial effects of exercise, and serving as messengers of intercellular communication and as carriers for research strategies of many diseases, we propose that exosomes could be a potential research direction or strategies of sarcopenia in the future.

Rong, S., Wang, L., Peng, Z., Liao, Y., Li, D., Yang, X., Nuessler, A. K., Liu, L., Bao, W., and Yang, W. ( 2020) The mechanisms and treatments for sarcopenia: could exosomes be a perspective research strategy in the future?, Journal of Cachexia, Sarcopenia and Muscle, 11, 348– 365. https://doi.org/10.1002/jcsm.12536.

ABSTRACT | PDF |

 

     Article first published online:  08 January 2020

Shuang Rong, Liangliang Wang, Zhao Peng, Yuxiao Liao, Dan Li, Xuefeng Yang, Andreas K. Nuessler, Liegang Liu, Wei Bao, Wei Yang

Nutrition interventions to treat low muscle mass in cancer
Many patients with cancer experience poor nutritional status, which detrimentally impacts clinical outcomes. Poor nutritional status in cancer is primarily manifested by severe muscle mass (MM) depletion, which may occur at any stage (from curative to palliative) and often co‐exists with obesity. The objective of this article was to discuss gaps and opportunities related to the role of nutrition in preventing and reversing low MM in cancer. It also provides a narrative review of relevant nutritional interventions for patients capable of oral intake. The impact of nutrition interventions to prevent/treat low MM in cancer is not well understood, potentially due to the limited number of studies and of clinically viable, accurate body composition assessment tools. Additionally, the type of study designs, inclusion criteria, length of intervention, and choice of nutritional strategies have not been optimal, likely underestimating the anabolic potential of nutrition interventions. Nutrition studies are also often of short duration, and interventions that adapt to the metabolic and behavioural changes during the clinical journey are needed. We discuss energy requirements (25–30 kcal/kg/day) and interventions of protein (1.0–1.5 g/kg/day), branched‐chain amino acids (leucine: 2–4 g/day), β‐hydroxy β‐methylbutyrate (3 g/day), glutamine (0.3 g/kg/day), carnitine (4–6 g/day), creatine (5 g/day), fish oil/eicosapentanoic acid (2.0–2.2 g/day EPA and 1.5 g/day DHA), vitamin/minerals (e.g. vitamin D: 600–800 international units per day), and multimodal approaches (nutrition, exercise, and pharmaceutical) to countermeasure low MM in cancer. Although the evidence is variable by modality type, interventions were generally not specifically studied in the context of cancer. Understanding patients' nutritional requirements could lead to targeted prescriptions to prevent or attenuate low MM in cancer, with the overall aim of minimizing muscle loss during anti‐cancer therapy and maximizing muscle anabolism during recovery. It is anticipated that this will, in turn, improve overall health and prognostication including tolerance to treatment and survival. However, oncology‐specific interventions with more robust study designs are needed to facilitate these goals.

Prado, C. M., Purcell, S. A., and Laviano, A. ( 2020) Nutrition interventions to treat low muscle mass in cancer, Journal of Cachexia, Sarcopenia and Muscle, 11, 366– 380. https://doi.org/10.1002/jcsm.12525.

ABSTRACT | PDF |

 

     Article first published online:  22 February 2020

Goran Loncar, Natasa Cvetinovic, Mitja Lainscak, Andjelka Isaković, Stephan von Haehling

Bone in heart failure
There is an increasing interest in osteoporosis and reduced bone mineral density affecting not only post‐menopausal women but also men, particularly with coexisting chronic diseases. Bone status in patients with stable chronic heart failure (HF) has been rarely studied so far. HF and osteoporosis are highly prevalent aging‐related syndromes that exact a huge impact on society. Both disorders are common causes of loss of function and independence, and of prolonged hospitalizations, presenting a heavy burden on the health care system. The most devastating complication of osteoporosis is hip fracture, which is associated with high mortality risk and among those who survive, leads to a loss of function and independence often necessitating admission to long‐term care. Current HF guidelines do not suggest screening methods or patient education in terms of osteoporosis or osteoporotic fracture. This review may serve as a solid base to discuss the need for bone health evaluation in HF patients.

Loncar, G., Cvetinovic, N., Lainscak, M., Isaković, A., and von Haehling, S. ( 2020) Bone in heart failure, Journal of Cachexia, Sarcopenia and Muscle, 11, 381– 393. https://doi.org/10.1002/jcsm.12516.

ABSTRACT | PDF |

 

     Article first published online:  21 December 2019

Jack O. Garnham, Lee D. Roberts, Ever Espino‐Gonzalez, Anna Whitehead, Peter P. Swoboda, Aaron Koshy, John Gierula, Maria F. Paton, Richard M. Cubbon, Mark T. Kearney, Stuart Egginton, T. Scott Bowen, Klaus K. Witte

Chronic heart failure with diabetes mellitus is characterized by a severe skeletal muscle pathology
Background
Patients with coexistent chronic heart failure (CHF) and diabetes mellitus (DM) demonstrate greater exercise limitation and worse prognosis compared with CHF patients without DM, even when corrected for cardiac dysfunction. Understanding the origins of symptoms in this subgroup may facilitate development of targeted treatments. We therefore characterized the skeletal muscle phenotype and its relationship to exercise limitation in patients with diabetic heart failure (D‐HF).
Methods
In one of the largest muscle sampling studies in a CHF population, pectoralis major biopsies were taken from age‐matched controls (n = 25), DM (n = 10), CHF (n = 52), and D‐HF (n = 28) patients. In situ mitochondrial function and reactive oxygen species, fibre morphology, capillarity, and gene expression analyses were performed and correlated to whole‐body exercise capacity.
Results
Mitochondrial respiration, content, coupling efficiency, and intrinsic function were lower in D‐HF patients compared with other groups (P < 0.05). A unique mitochondrial complex I dysfunction was present in D‐HF patients only (P < 0.05), which strongly correlated to exercise capacity (R2 = 0.64; P < 0.001). Mitochondrial impairments in D‐HF corresponded to higher levels of mitochondrial reactive oxygen species (P < 0.05) and lower gene expression of anti‐oxidative enzyme superoxide dismutase 2 (P < 0.05) and complex I subunit NDUFS1 (P < 0.05). D‐HF was also associated with severe fibre atrophy (P < 0.05) and reduced local fibre capillarity (P < 0.05).
Conclusions
Patients with D‐HF develop a specific skeletal muscle pathology, characterized by mitochondrial impairments, fibre atrophy, and derangements in the capillary network that are linked to exercise intolerance. These novel preliminary data support skeletal muscle as a potential therapeutic target for treating patients with D‐HF.

Garnham, J. O., Roberts, L. D., Espino‐Gonzalez, E., Whitehead, A., Swoboda, P. P., Koshy, A., Gierula, J., Paton, M. F., Cubbon, R. M., Kearney, M. T., Egginton, S., Bowen, T. S., and Witte, K. K. ( 2020) Chronic heart failure with diabetes mellitus is characterized by a severe skeletal muscle pathology, Journal of Cachexia, Sarcopenia and Muscle, 11, 394– 404. https://doi.org/10.1002/jcsm.12515.

ABSTRACT | PDF |

 

     Article first published online:  09 January 2020

Eberhard Lurz, Hiten Patel, Gerald Lebovic, Claudia Quammie, Jessica P. Woolfson, Manuela Perez, Amanda Ricciuto, Paul W. Wales, Binita M. Kamath, Govind B. Chavhan, Peter Jüni, Vicky L. Ng

Paediatric reference values for total psoas muscle area
Background
Sarcopenia, the unintentional loss of skeletal muscle mass, is associated with poor outcomes in adult patient populations. In adults, sarcopenia is often ascertained by cross‐sectional imaging of the psoas muscle area (PMA). Although children with chronic medical illnesses may be at increased risk for muscle loss because of nutritional deficiencies, physical deconditioning, endocrine anomalies, and systemic inflammation, consistent quantitative definitions for sarcopenia in children are lacking. We aimed to generate paediatric reference values for PMA at two intervertebral lumbar levels, L3–4 and L4–5.
Methods
In this cross‐sectional study, we analysed abdominal computed tomography scans of consecutive children presenting to the emergency department. Participants were children 1–16 years who required abdominal cross‐sectional imaging after paediatric trauma between January 1, 2005 and December 31, 2015 in a large Canadian quaternary care centre. Children with a documented chronic medical illness or an acute spinal trauma at presentation were excluded. Total PMA (tPMA) at levels L3–4 and L4–5 were measured in square millimetres (mm2) as the sum of left and right PMA. Age‐specific and sex‐specific tPMA percentile curves were modelled using quantile regression.
Results
Computed tomography images from 779 children were included. Values of tPMA at L4–5 were significantly larger than at L3–4 at all ages, but their correlation was high for both girls (r = 0.95) and boys (r = 0.98). Amongst girls, tPMA 50th percentile values ranged from 365 to 2336 mm2 at L3–4 and from 447 to 2704 mm2 for L4–5. Amongst boys, 50th percentile values for tPMA ranged between 394 and 3050 mm2 at L3–4 and from 498 to 3513 mm2 at L4–5. Intraclass correlation coefficients were excellent at L3–4 (0.97, 95% CI 0.94 to 0.981) and L4–5 (0.99, 95% CI 0.986 to 0.995). Weight and tPMA were correlated, stratified by sex for boys (L3–4 r = 0.90; L4–5 r = 0.90) and for girls (L3–4 r = 0.87; L4–5 r = 0.87). An online application was subsequently developed to easily calculate age‐specific and sex‐specific z‐scores and percentiles.
Conclusions
We provide novel paediatric age‐specific and sex‐specific growth curves for tPMA at intervertebral L3–4 and L4–5 levels for children between the ages of 1‐16 years. Together with an online tool (https://ahrc‐apps.shinyapps.io/sarcopenia/), these tPMA curves should serve as a reference enabling earlier identification and targeted intervention of sarcopenia in children with chronic medical conditions.

Lurz, E., Patel, H., Lebovic, G., Quammie, C., Woolfson, J. P., Perez, M., Ricciuto, A., Wales, P. W., Kamath, B. M., Chavhan, G. B., Jüni, P., and Ng, V. L. ( 2020) Paediatric reference values for total psoas muscle area, Journal of Cachexia, Sarcopenia and Muscle, 11, 405– 414. https://doi.org/10.1002/jcsm.12514.

ABSTRACT | PDF |

 

     Article first published online:  08 January 2020

Asier Mañas, Borja del Pozo‐Cruz, Irene Rodríguez‐Gómez, José Losa‐Reyna, Leocadio Rodríguez‐Mañas, Francisco J. García‐García, Ignacio Ara

Which one came first: movement behavior or frailty? A cross‐lagged panel model in the Toledo Study for Healthy Aging
Background
There has been limited longitudinal assessment of the relationship between moderate‐to‐vigorous physical activity (MVPA) and sedentary behaviour (SB) with frailty, and no studies have explored the possibility of reverse causality. This study aimed to determine the potential bidirectionality of the relationship between accelerometer‐assessed MVPA, SB, and frailty over time in older adults.
Methods
Participants were from the Toledo Study for Healthy Aging. We analysed 186 older people aged 67 to 90 (76.7 ± 3.9; 52.7% female participants) over a 4‐year period. Time spent in SB and MVPA was assessed by accelerometry. Frailty Trait Scale was used to determine frailty levels. A cross‐lagged panel model design was used to test the reciprocal relationships between MVPA/SB and frailty.
Results
Frailty Trait Scale score changed from 35.4 to 43.8 points between the two times (P < 0.05). We also found a reduction of 7 min/day in the time spent on MVPA (P < 0.05), and participants tended to spend more time on SB (P = 0.076). Our analyses revealed that lower levels of initial MVPA predicted higher levels of later frailty [std. β = −0.126; confidence interval (CI) = −0.231, −0.021; P < 0.05], whereas initial spent time on SB did not predict later frailty (std. β = −0.049; CI = −0.185, 0.087; P = 0.48). Conversely, an initial increased frailty status predicted higher levels of later SB (std. β = 0.167; CI = 0.026, 0.307; P < 0.05) but not those of MVPA (std. β = 0.071; CI = −0.033, 0.175; P = 0.18).
Conclusions
Our observations suggest that the relationship between MVPA/SB and frailty is unidirectional: individuals who spent less time on MVPA at baseline are more likely to increase their frailty score, and individuals who are more frail are more likely to spent more time on SB at follow‐up. Interventions and policies should aim to increase MVPA levels from earlier stages to promote successful aging.

Mañas, A., del Pozo‐Cruz, B., Rodríguez‐Gómez, I., Losa‐Reyna, J., Rodríguez‐Mañas, L., García‐García, F. J., and Ara, I. ( 2020) Which one came first: movement behavior or frailty? A cross‐lagged panel model in the Toledo Study for Healthy Aging, Journal of Cachexia, Sarcopenia and Muscle, 11, 415– 423. https://doi.org/10.1002/jcsm.12511.

ABSTRACT | PDF |

 

     Article first published online:  11 February 2020

Chris Burtin, Jacques Bezuidenhout, Karin J.C. Sanders, Anne‐Marie C. Dingemans, Annemie M.W.J. Schols, Stephanie T.H. Peeters, Martijn A. Spruit, Dirk K.M. De Ruysscher

Handgrip weakness, low fat‐free mass, and overall survival in non‐small cell lung cancer treated with curative‐intent radiotherapy
Background
Assessment of handgrip strength and fat‐free mass provides quick and objective information on muscle performance and mass that might complement subjective World Health Organization Performance Status (WHO PS). We investigated to what extent the presence of pre‐treatment handgrip weakness and low fat‐free mass index (FFMI) provides additional prognostic information on top of well‐established prognostic factors (including WHO PS) in non‐small cell lung cancer (NSCLC) patients selected for curative‐intent (chemo)radiation.
Methods
Prospectively, patients with early and locally advanced NSCLC (stages I‐III) treated with (chemo)radiation were enrolled. Handgrip weakness and low FFMI, derived from bioelectrical impedance analysis, were defined using normative values and were correlated with overall survival (OS).
Results
We included 936 patients (age 68 ± 10 years; 64% male; 19% stage I, 9% stage II, and 72% stage III disease; 26% handgrip weakness; 27% low FFMI). In patients with good performance status (WHO PS 0 or 1), handgrip weakness and low FFMI were significant prognostic factors for OS, after adjustment for age, gender, disease stage, and co‐morbidities. The combined presence of handgrip weakness and low FFMI was a strong prognostic factor for OS when compared with patients with normal handgrip strength and FFMI (hazard ratio: 1.79, 95% confidence interval: 1.34–2.40, P < 0.0001). In patients with impaired performance status (WHO PS ≥ 2, 19% of sample), handgrip weakness and low FFMI were not related to OS.
Conclusions
In early and locally advanced NSCLC patients treated with curative‐intent (chemo)radiation who have good WHO PS, patients with combined handgrip weakness and low FFMI have the worst prognosis.

Burtin, C., Bezuidenhout, J., Sanders, K. J. C., Dingemans, A.‐M. C., Schols, A. M. W. J., Peeters, S. T. H., Spruit, M. A., and De Ruysscher, D. K. M. ( 2020) Handgrip weakness, low fat‐free mass, and overall survival in non‐small cell lung cancer treated with curative‐intent radiotherapy, Journal of Cachexia, Sarcopenia and Muscle, 11, 424– 431. https://doi.org/10.1002/jcsm.12526.

ABSTRACT | PDF |

 

     Article first published online:  08 January 2020

Jung‐Yeon Choi, Kwang‐il Kim, YoungRok Choi, Sang‐Hoon Ahn, Eunyoung Kang, Heung‐Kwon Oh, Duck‐Woo Kim, Eun‐Kyu Kim, Yoo‐Seok Yoon, Sung‐Bum Kang, Hyung‐Ho Kim, Ho‐Seong Han, Cheol‐Ho Kim

Comparison of multidimensional frailty score, grip strength, and gait speed in older surgical patients
Background
Frail older adults are at increased risk of post‐operative morbidity compared with robust counterparts. Simple methods testing frailty such as grip strength or gait speed have shown promising results for predicting post‐operative outcome, but there is a debate regarding the most appropriate and precise frailty assessment method. We compared the predictive value of multidimensional frailty score (MFS) with grip strength, gait speed, or conventional risk stratification tool for predicting post‐operative complications in older surgical patients.
Methods
From January 2016 to June 2017, 648 older surgical patients (age ≥ 65 years) were included for analysis. MFS was calculated based on the preoperative comprehensive geriatric assessment. Grip strength and gait speed were measured before surgery. The primary outcome was a composite of post‐operative complications (e.g. pneumonia, urinary tract infection, delirium, acute pulmonary thromboembolism, and unplanned intensive care unit admission). The secondary outcome was the 6 month all‐cause mortality.
Results
Among 648 patients (mean age 76.6 ± 5.4 years, 52.8% female), 66 (10.2%) patients experienced post‐operative complications, and the 6 month mortality was 3.9% (n = 25). Grip strength, gait speed, MFS, and American Society of Anesthesiologists (ASA) classification could predict post‐operative complication but only MFS (hazard ratio = 1.581, 95% confidence interval 1.276–1.959, P < 0.001) could predict 6 month mortality after adjustment. MFS (C‐index = 0.750) had a superior prognostic utility compared with age (0.638, P = 0.008), grip strength (0.566, P < 0.001), and ASA classification (0.649, P = 0.004). MFS improved the predictive value on age [C‐index of 0.638 (age) vs. 0.758 (age + MFS), P < 0.001] and ASA classification [C‐index of 0.649 (ASA) vs. 0.765 (ASA + MFS), P < 0.001] for post‐operative complication; however, gait speed or grip strength did not provide additional prognostic value in both age and ASA.
Conclusions
Multidimensional frailty score based on preoperative comprehensive geriatric assessment showed better utility than age, grip strength, gait speed, or ASA classification for predicting post‐operative complication and 6 month mortality. MFS also showed incremental predictive ability for post‐operative complications with the addition of age and ASA classification. Accordingly, MFS is superior to grip strength or gait speed for predicting complications among older surgical patients.

Choi, J.‐Y., Kim, K.‐i., Choi, Y. R., Ahn, S.‐H., Kang, E., Oh, H.‐K., Kim, D.‐W., Kim, E.‐K., Yoon, Y.‐S., Kang, S.‐B., Kim, H.‐H., Han, H.‐S., and Kim, C.‐H. ( 2020) Comparison of multidimensional frailty score, grip strength, and gait speed in older surgical patients, Journal of Cachexia, Sarcopenia and Muscle, 11, 432– 440. https://doi.org/10.1002/jcsm.12509.

ABSTRACT | PDF |

 

     Article first published online:  26 December 2019

Yu‐Ri Choe, Ju‐Ri Jeong, Yeon‐Pyo Kim

Grip strength mediates the relationship between muscle mass and frailty
Background
Although sarcopenia and frailty are important diseases in geriatrics, few studies have investigated the association between the two diseases. Thus, this study aimed to examine the relationship between two components of sarcopenia (muscle mass and muscle function) and frailty.
Methods
In total, 997 Korean older adults (456 men and 541 women) were included in this cross‐sectional observational study. We used a polynomial linear regression analysis to obtain standardized sex, age, and height‐adjusted appendicular skeletal muscle mass (zASM), as well as to standardized sex, age, and height‐adjusted grip strength (zGS). We then performed a causal mediation analysis to confirm the relationship between zASM and frailty.
Results
In both men and women, zGS mediated the relationship between zASM and frailty (average causal mediation effect in men: −0.096 {−0.159 to −0.050}; in women: −0.053 {−0.098 to −0.010}). For every one‐point increase in zGS score, the relative risk of a one‐point increase in frailty was reduced by 21% in men (e−0.238 = 0.788) and by 11% in women (e−0.113 = 0.893).
Conclusions
In this study on Korean older adults, muscle mass did not have a direct effect on frailty but had an indirect effect through altered muscle function.

Choe, Y.‐R., Jeong, J.‐R., and Kim, Y.‐P. ( 2020) Grip strength mediates the relationship between muscle mass and frailty, Journal of Cachexia, Sarcopenia and Muscle, 11, 441– 451. https://doi.org/10.1002/jcsm.12510.

ABSTRACT | PDF |

 

     Article first published online:  11 December 2019

Wouter R.P.H. van de Worp, Annemie M.W.J. Schols, Anne‐Marie C. Dingemans, Céline M.H. Op den Kamp, Juliette H.R.J. Degens, Marco C.J.M. Kelders, Susan Coort, Henry C. Woodruff, Gueorqui Kratassiouk, Annick Harel‐Bellan, Jan Theys, Ardy van Helvoort, Ramon C.J. Langen

Identification of microRNAs in skeletal muscle associated with lung cancer cachexia
Background
Cachexia, highly prevalent in patients with non‐small cell lung cancer (NSCLC), impairs quality of life and is associated with reduced tolerance and responsiveness to cancer therapy and decreased survival. MicroRNAs (miRNAs) are small non‐coding RNAs that play a central role in post‐transcriptional gene regulation. Changes in intramuscular levels of miRNAs have been implicated in muscle wasting conditions. Here, we aimed to identify miRNAs that are differentially expressed in skeletal muscle of cachectic lung cancer patients to increase our understanding of cachexia and to allow us to probe their potential as therapeutic targets.
Methods
A total of 754 unique miRNAs were profiled and analysed in vastus lateralis muscle biopsies of newly diagnosed treatment‐naïve NSCLC patients with cachexia (n = 8) and age‐matched and sex‐matched healthy controls (n = 8). miRNA expression analysis was performed using a TaqMan MicroRNA Array. In silico network analysis was performed on all significant differentially expressed miRNAs. Differential expression of the top‐ranked miRNAs was confirmed using reverse transcription–quantitative real‐time PCR in an extended group (n = 48) consisting of NSCLC patients with (n = 15) and without cachexia (n = 11) and healthy controls (n = 22). Finally, these miRNAs were subjected to univariate and multivariate Cox proportional hazard analysis using overall survival and treatment‐induced toxicity data obtained during the follow‐up of this group of patients.
Results
We identified 28 significant differentially expressed miRNAs, of which five miRNAs were up‐regulated and 23 were down‐regulated. In silico miRNA‐target prediction analysis showed 158 functional gene targets, and pathway analysis identified 22 pathways related to the degenerative or regenerative processes of muscle tissue. Subsequently, the expression of six top‐ranked miRNAs was measured in muscle biopsies of the entire patient group. Five miRNAs were detectable with reverse transcription–quantitative real‐time PCR analysis, and their altered expression (expressed as fold change, FC) was confirmed in muscle of cachectic NSCLC patients compared with healthy control subjects: miR‐424‐5p (FC = 4.5), miR‐424‐3p (FC = 12), miR‐450a‐5p (FC = 8.6), miR‐144‐5p (FC = 0.59), and miR‐451a (FC = 0.57). In non‐cachectic NSCLC patients, only miR‐424‐3p was significantly increased (FC = 5.6) compared with control. Although the statistical support was not sufficient to imply these miRNAs as individual predictors of overall survival or treatment‐induced toxicity, when combined in multivariate analysis, miR‐450‐5p and miR‐451a resulted in a significant stratification between short‐term and long‐term survival.
Conclusions
We identified differentially expressed miRNAs putatively involved in lung cancer cachexia. These findings call for further studies to investigate the causality of these miRNAs in muscle atrophy and the mechanisms underlying their differential expression in lung cancer cachexia.

Worp, W. R. P. H. v. d., Schols, A. M. W. J., Dingemans, A.‐M. C., Op den Kamp, C. M. H., Degens, J. H. R. J., Kelders, M. C. J. M., Coort, S., Woodruff, H. C., Kratassiouk, G., Harel‐Bellan, A., Theys, J., van Helvoort, A., and Langen, R. C. J. ( 2020) Identification of microRNAs in skeletal muscle associated with lung cancer cachexia, Journal of Cachexia, Sarcopenia and Muscle, 11, 452– 463. https://doi.org/10.1002/jcsm.12512.

ABSTRACT | PDF |

 

     Article first published online:  03 January 2020

Kristoffer Svensson, Samuel A. LaBarge, Abha Sathe, Vitor F. Martins, Shahriar Tahvilian, Jennifer M. Cunliffe, Roman Sasik, Sushil K. Mahata, Gretchen A. Meyer, Andrew Philp, Larry L. David, Samuel R. Ward, Carrie E. McCurdy, Joseph E. Aslan, Simon Schenk

p300 and cAMP response element‐binding protein‐binding protein in skeletal muscle homeostasis, contractile function, and survival
Background
Reversible ε‐amino acetylation of lysine residues regulates transcription as well as metabolic flux; however, roles for specific lysine acetyltransferases in skeletal muscle physiology and function are unknown. In this study, we investigated the role of the related acetyltransferases p300 and cAMP response element‐binding protein‐binding protein (CBP) in skeletal muscle transcriptional homeostasis and physiology in adult mice.
Methods
Mice with skeletal muscle‐specific and inducible knockout of p300 and CBP (PCKO) were generated by crossing mice with a tamoxifen‐inducible Cre recombinase expressed under the human α‐skeletal actin promoter with mice having LoxP sites flanking exon 9 of the Ep300 and Crebbp genes. Knockout of PCKO was induced at 13–15 weeks of age via oral gavage of tamoxifen for 5 days to both PCKO and littermate control [wildtype (WT)] mice. Body composition, food intake, and muscle function were assessed on day 0 (D0) through 5 (D5). Microarray and tandem mass tag mass spectrometry analyses were performed to assess global RNA and protein levels in skeletal muscle of PCKO and WT mice.
Results
At D5 after initiating tamoxifen treatment, there was a reduction in body weight (−15%), food intake (−78%), stride length (−46%), and grip strength (−45%) in PCKO compared with WT mice. Additionally, ex vivo contractile function [tetanic tension (kPa)] was severely impaired in PCKO vs. WT mice at D3 (~70–80% lower) and D5 (~80–95% lower) and resulted in lethality within 1 week—a phenotype that is reversed by the presence of a single allele of either p300 or CBP. The impaired muscle function in PCKO mice was paralleled by substantial transcriptional alterations (3310 genes; false discovery rate < 0.1), especially in gene networks central to muscle contraction and structural integrity. This transcriptional uncoupling was accompanied by changes in protein expression patterns indicative of impaired muscle function, albeit to a smaller magnitude (446 proteins; fold‐change > 1.25; false discovery rate < 0.1).
Conclusions
These data reveal that p300 and CBP are required for the control and maintenance of contractile function and transcriptional homeostasis in skeletal muscle and, ultimately, organism survival. By extension, modulating p300/CBP function may hold promise for the treatment of disorders characterized by impaired contractile function in humans.

Svensson, K., LaBarge, S. A., Sathe, A., Martins, V. F., Tahvilian, S., Cunliffe, J. M., Sasik, R., Mahata, S. K., Meyer, G. A., Philp, A., David, L. L., Ward, S. R., McCurdy, C. E., Aslan, J. E., and Schenk, S. ( 2020) p300 and cAMP response element‐binding protein‐binding protein are essential for skeletal muscle homeostasis, contractile function, and survival, Journal of Cachexia, Sarcopenia and Muscle, 11, 464– 477. https://doi.org/10.1002/jcsm.12522.

ABSTRACT | PDF |

 

     Article first published online:  208 January 2020

Carmen Sánchez‐Castellano, Sagrario Martín‐Aragón, Paloma Bermejo‐Bescós, Nieves Vaquero‐Pinto, Carmen Miret‐Corchado, Ana Merello de Miguel, Alfonso José Cruz‐Jentoft

Biomarkers of sarcopenia in very old patients with hip fracture
Background
Hip fracture is both a cause and a consequence of sarcopenia. Older persons with sarcopenia have an increased risk of falling, and the prevalence of sarcopenia may be increased in those who suffer a hip fracture. The aim of this study was to explore potential biomarkers (neuromuscular and peripheral pro‐inflammatory and oxidative stress markers) that may be associated with sarcopenia in very old persons with hip fracture.
Methods
We recruited 150 consecutive patients ≥80 years old admitted to an orthogeriatric unit for an osteoporotic hip fracture. Muscle mass was assessed pre‐operatively using bioelectrical impedance analysis; Janssen's (J) and Masanés' (M) reference cut‐off points were used to define low muscle mass. Muscle strength was assessed with handgrip strength (Jamar's dynamometer). Sarcopenia was defined by having both low muscle mass and strength and using the European Working Group on Sarcopenia in Older People 2 definition of probable sarcopenia (low grip strength). Peripheral markers—pro‐inflammatory and oxidative stress parameters—were determined either in the plasma or in the erythrocyte fraction obtained from peripheral whole blood of every patient pre‐operatively.
Results
Mean age was 87.6 ± 4.9 years, and 78.7% were women. The prevalence of sarcopenia was 11.5% with Janssen's, 34.9% with Masanés' cut‐offs, and 93.3% with the European Working Group on Sarcopenia in Older People 2 definition of probable sarcopenia. Among the four pro‐inflammatory cytokines tested in plasma, only tumour necrosis factor‐α was different (lower) in sarcopenic than in non‐sarcopenic participants using both muscle mass cut‐offs (J 7.9 ± 6.2 vs. 8.3 ± 5.8, M 6.8 ± 4.7 vs. 9.1 ± 6.2). Erythrocyte glutathione system showed a non‐significant tendency to lower glutathione levels and glutathione/oxidized glutathione ratios in sarcopenic participants compared with non‐sarcopenic subjects. Catalase activity was also lower in sarcopenic participants (J 2904 ± 1429 vs. 3329 ± 1483, M 3037 ± 1430 vs. 3431 ± 1498). No significant differences were found between groups in chymotrypsin‐like activity of the 20S proteasome, superoxide dismutase, glutathione peroxidase and butyrylcholinesterase activity, C‐terminal agrin fragment, interferon‐γ, or interleukin‐1β.
Conclusions
The prevalence of sarcopenia in patients with hip fracture varies according to the definition and the muscle mass reference cut‐off points used. We did not find differences in most neuromuscular, pro‐inflammatory, or oxidative stress markers, except for lower peripheral tumour necrosis factor‐α levels and catalase activity in sarcopenic participants, which may be markers of an early inflammatory reaction that is hampered in sarcopenic patients.

Sánchez‐Castellano, C., Martín‐Aragón, S., Bermejo‐Bescós, P., Vaquero‐Pinto, N., Miret‐Corchado, C., Merello de Miguel, A., and Cruz‐Jentoft, A. J. ( 2020) Biomarkers of sarcopenia in very old patients with hip fracture, Journal of Cachexia, Sarcopenia and Muscle, 11, 478– 486. https://doi.org/10.1002/jcsm.12508.

ABSTRACT | PDF |

 

     Article first published online:  13 January 2020

Mei‐Man Lee, Susan A. Jebb, Jason Oke, Carmen Piernas

Reference values for skeletal muscle mass and fat mass measured by bioelectrical impedance in 390 565 UK adults
Background
Loss of skeletal muscle mass (SMM) increases the risk of frailty and, together with excess fat mass (FM), is a risk factor for cardio‐metabolic disease. However, use of body composition measurements in nutritional surveillance and routine clinical practice is limited by the lack of reference data. Our aim was to produce age‐specific and sex‐specific reference values for SMM and FM in the White ethnic adult population in the UK. Secondary objectives were to examine the tracking over time using a subsample of the population with repeated measures of body composition and to assess the validity of these reference values in different ethnic subgroups.
Methods
We used data from segmental bioelectrical impedance analysis (BIA) in 390 565 participants, aged 40–69 years, in the UK Biobank, and data from dual‐energy X‐ray absorptiometry from n = 905 participants to validate the BIA measurements. SMM was calculated as the sum of the predicted muscle mass from the limbs. The LMS method was used to produce percentile curves for the SMM index (SMMI = SMM/height2) and the FM index (FMI = FM/height2). We investigated the validity of the White ethnic reference values by plotting z‐scores (99.7% confidence interval) from Black and Asian groups to check if their confidence interval included zero. Longitudinal trajectories were predicted based on the baseline z‐scores and the correlation between repeated measurements at follow‐up.
Results
The percentile curves show that SMMI declines in men from the age of 40, whereas in women, SMMI is more stable and decreases only slightly among women in the higher percentiles. FMI increases with age in both men and women. Women have higher FMI and lower SMMI than men in all age groups. The validity of the White‐based reference values for non‐White ethnic groups is poor. Longitudinal trajectories in body composition in the subsample of participants with a follow‐up assessment show regression towards the mean in both men and women, with some evidence of declining SMMI only among men. The predicted 90% limits for the expected 5 year trajectories of SMMI and FMI can be used to identify people with unusual trajectories and in clinical practice to identify and track individuals at risk of excessive loss of SMM.
Conclusions
These body composition reference values developed from BIA in a middle/older‐aged healthy White ethnic population in the UK could be used as a simple assessment tool for nutritional surveillance and to identify individuals with low SMMI or high FMI who may be at increased risk of disease and/or frailty.

Lee, M.‐M., Jebb, S. A., Oke, J., and Piernas, C. ( 2020) Reference values for skeletal muscle mass and fat mass measured by bioelectrical impedance in 390 565 UK adults, Journal of Cachexia, Sarcopenia and Muscle, 11, 487– 496. https://doi.org/10.1002/jcsm.12523.

ABSTRACT | PDF |

 

     Article first published online:  21 December 2019

Il‐Young Jang, Eunju Lee, Heayon Lee, Hyungchul Park, Sunyoung Kim, Kwang‐il Kim, Hee‐Won Jung, Dae Hyun Kim

Characteristics of sarcopenia by European consensuses and a phenotype score
Background
We aimed to assess the clinical characteristics of sarcopenia by the original and revised European Working Group on Sarcopenia in Older People (EWGSOP 1 and 2), and to propose a new sarcopenia phenotype score (SPS) to improve relevance of clinical outcomes.
Methods
Analyses were performed in 1408 older adults of the Aging Study of PyeongChang Rural Area, a community‐based cohort in Korea. For sarcopenia definitions, we used EWGSOP 1, EWGSOP 2, and SPS, a new index counting number of abnormal domains among components of grip strength, gait speed, or muscle mass. Frailty status by the frailty index and the Cardiovascular Health Study frailty score was compared with sarcopenia measures. Prediction ability for composite outcome combining death and institutionalization due to functional decline was assessed among sarcopenia measures.
Results
Generally, sarcopenia spectrum by both EWGSOP 1 and 2 was associated with worse functional status in parameters of geriatric assessments. However, population who were considered as sarcopenic by EWGSOP 1, but not by EWGSOP 2, showed increased risk of composite outcome and worse frailty status, compared with people who were classified as not sarcopenic by both EWGSOP 1 and 2. With SPS, dose–response relationship was observed with both frailty status and outcome prediction. Prediction for composite outcome was better in SPS than in EWGSOP 2 classification.
Conclusions
A new SPS might be used to classify sarcopenic burden in older adults to resolve possible inconsistencies in phenotype correlation and outcome prediction of EWGSOP 2 criteria.

Jang, I.‐Y., Lee, E., Lee, H., Park, H., Kim, S., Kim, K.‐i., Jung, H.‐W., and Kim, D. H. ( 2020) Characteristics of sarcopenia by European consensuses and a phenotype score, Journal of Cachexia, Sarcopenia and Muscle, 11, 497– 504. https://doi.org/10.1002/jcsm.12507.

ABSTRACT | PDF |

 

     Article first published online:  27 December 2019

Mirko Signorelli, Burcu Ayoglu, Camilla Johansson, Hanns Lochmüller, Volker Straub, Francesco Muntoni, Erik Niks, Roula Tsonaka, Anja Persson, Annemieke Aartsma‐Rus, Peter Nilsson, Cristina Al‐Khalili Szigyarto, Pietro Spitali

Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy
Background
Duchenne muscular dystrophy (DMD) is a fatal disease for which no cure is available. Clinical trials have shown to be largely underpowered due to inter‐individual variability and noisy outcome measures. The availability of biomarkers able to anticipate clinical benefit is highly needed to improve clinical trial design and facilitate drug development.
Methods
In this study, we aimed to appraise the value of protein biomarkers to predict prognosis and monitor disease progression or treatment outcome in patients affected by DMD. We collected clinical data and 303 blood samples from 157 DMD patients in three clinical centres; 78 patients contributed multiple blood samples over time, with a median follow‐up time of 2 years. We employed linear mixed models to identify biomarkers that are associated with disease progression, wheelchair dependency, and treatment with corticosteroids and performed survival analysis to find biomarkers whose levels are associated with time to loss of ambulation.
Results
Our analysis led to the identification of 21 proteins whose levels significantly decrease with age and nine proteins whose levels significantly increase. Seven of these proteins are also differentially expressed in non‐ambulant patients, and three proteins are differentially expressed in patients treated with glucocorticosteroids. Treatment with corticosteroids was found to partly counteract the effect of disease progression on two biomarkers, namely, malate dehydrogenase 2 (MDH2, P = 0.0003) and ankyrin repeat domain 2 (P = 0.0005); however, patients treated with corticosteroids experienced a further reduction on collagen 1 serum levels (P = 0.0003), especially following administration of deflazacort. A time to event analysis allowed to further support the use of MDH2 as a prognostic biomarker as it was associated with an increased risk of wheelchair dependence (P = 0.0003). The obtained data support the prospective evaluation of the identified biomarkers in natural history and clinical trials as exploratory biomarkers.
Conclusions
We identified a number of serum biomarkers associated with disease progression, loss of ambulation, and treatment with corticosteroids. The identified biomarkers are promising candidate prognostic and surrogate biomarkers, which may support drug developers if confirmed in prospective studies. The serum levels of MDH2 are of particular interest, as they correlate with disease stage and response to treatment with corticosteroids, and are also associated with the risk of wheelchair dependency and pulmonary function.

Signorelli, M., Ayoglu, B., Johansson, C., Lochmüller, H., Straub, V., Muntoni, F., Niks, E., Tsonaka, R., Person, A., Aartsma‐Rus, A., Nilsson, P., Al‐Khalili Szigyarto, C., and Spitali, P. ( 2020) Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy, Journal of Cachexia, Sarcopenia and Muscle, 11, 505– 517. https://doi.org/10.1002/jcsm.12517.

ABSTRACT | PDF |

 

     Article first published online:  21 January 2020

Michel Abou‐Samra, Camille M. Selvais, Raphael Boursereau, Sophie Lecompte, Laurence Noel, Sonia M. Brichard

AdipoRon, a new therapeutic prospect for Duchenne muscular dystrophy
Background
Adiponectin (ApN) is a hormone known to exhibit insulin‐sensitizing, fat‐burning, and anti‐inflammatory properties in several tissues, including the skeletal muscle. Duchenne muscular dystrophy (DMD) is a devastating disease characterized by dystrophin deficiency with subsequent chronic inflammation, myofiber necrosis, and impaired regeneration. Previously, we showed that transgenic up‐regulation of ApN could significantly attenuate the dystrophic phenotype in mdx mice (model of DMD). Recently, an orally active ApN receptor agonist, AdipoRon, has been identified. This synthetic small molecule has the advantage of being more easily produced and administrable than ApN. The aim of this study was to investigate the potential effects of AdipoRon on the dystrophic muscle.
Methods
Four‐week‐old mdx mice (n = 6–9 per group) were orally treated with AdipoRon (mdx‐AR) for 8 weeks and compared with untreated (mdx) mice and to control (wild‐type) mice. In vivo functional tests were carried out to measure the global force and endurance of mice. Ex vivo biochemical and molecular analyses were performed to evaluate the pathophysiology of the skeletal muscle. Finally, in vitro tests were conducted on primary cultures of healthy and DMD human myotubes.
Results
AdipoRon treatment mitigated oxidative stress (−30% to 45% for 4‐hydroxy‐2‐nonenal and peroxiredoxin 3, P < 0.0001) as well as inflammation in muscles of mdx mice (−35% to 65% for interleukin 1 beta, tumour necrosis factor alpha, and cluster of differentiation 68, a macrophage maker, P < 0.0001) while increasing the anti‐inflammatory cytokine, interleukin 10 (~5‐fold, P < 0.0001). AdipoRon also improved the myogenic programme as assessed by a ~2‐fold rise in markers of muscle proliferation and differentiation (P < 0.01 or less vs. untreated mdx). Plasma lactate dehydrogenase and creatine kinase were reduced by 30–40% in mdx‐AR mice, reflecting less sarcolemmal damage (P < 0.0001). When compared with untreated mdx mice, mdx‐AR mice exhibited enhanced physical performance with an increase in both muscle force and endurance and a striking restoration of the running capacity during eccentric exercise. AdipoRon mainly acted through ApN receptor 1 by increasing AMP‐activated protein kinase signalling, which led to repression of nuclear factor‐kappa B, up‐regulation of utrophin (a dystrophin analogue), and a switch towards an oxidative and more resistant fibre phenotype. The effects of AdipoRon were then recapitulated in human DMD myotubes.
Conclusions
These results demonstrate that AdipoRon exerts several beneficial effects on the dystrophic muscle. This molecule could offer promising therapeutic prospect for managing DMD or other muscle and inflammatory disorders.

Abou‐Samra, M., Selvais, C. M., Boursereau, R., Lecompte, S., Noel, L., and Brichard, S. M. ( 2020) AdipoRon, a new therapeutic prospect for Duchenne muscular dystrophy, Journal of Cachexia, Sarcopenia and Muscle, 11, 518– 533. https://doi.org/10.1002/jcsm.12531.

ABSTRACT | PDF |

 

     Article first published online:  30 January 2020

Chueh‐Yi Huang, Yuh‐Cheng Yang, Tze‐Chien Chen, Jen‐Ruei Chen, Yu‐Jen Chen, Meng‐Hao Wu, Ya‐Ting Jan, Chih‐Long Chang, Jie Lee

Muscle loss during primary debulking surgery and chemotherapy predicts poor survival in advanced‐stage ovarian cancer
Background
Sarcopenia is commonly observed in patients with advanced‐stage epithelial ovarian cancer (EOC). However, the effect of body composition changes—during primary debulking surgery (PDS) and adjuvant platinum‐based chemotherapy—on outcomes of patients with advanced‐stage EOC is unknown. This study aimed to evaluate the association between body composition changes and outcomes of patients with stage III EOC treated with PDS and adjuvant platinum‐based chemotherapy.
Methods
Pre‐treatment and post‐treatment computed tomography (CT) images of 139 patients with stage III EOC were analysed. All CT images were contrast‐enhanced scans and were acquired according to a standardized protocol. The skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and total adipose tissue index were measured using CT images obtained at the L3 vertebral level. Predictors of overall survival were identified using Cox regression models.
Results
The median follow‐up was 37.9 months. The median duration between pre‐treatment and post‐treatment CT was 182 days (interquartile range: 161–225 days). Patients experienced an average SMI loss of 1.8%/180 days (95% confidence interval: −3.1 to −0.4; P = 0.01) and SMD loss of 1.7%/180 days (95% confidence interval: −3.3 to −0.03; P = 0.046). SMI and SMD changes were weakly correlated with body mass index changes (Spearman ρ for SMI, 0.15, P = 0.07; ρ for SMD, 0.02, P = 0.82). The modified Glasgow prognostic score was associated with SMI loss (odds ratio: 2.42, 95% confidence interval: 1.03–5.69; P = 0.04). The median time to disease recurrence was significantly shorter in patients with SMI loss ≥5% after treatment than in those with SMI loss <5% or gain (5.4 vs. 11.2 months, P = 0.01). Pre‐treatment SMI (1 cm2/m2 decrease; hazard ratio: 1.08, 95% confidence interval: 1.03–1.11; P = 0.002) and SMI change (1%/180 days decrease; hazard ratio: 1.04, 95% confidence interval: 1.01–1.08; P = 0.002) were independently associated with poorer overall survival. SMD, body mass index, and total adipose tissue index at baseline and changes were not associated with overall survival.
Conclusions
Skeletal muscle index decreased significantly during treatment and was independently associated with poor overall survival in patients with stage III EOC treated with PDS and adjuvant platinum‐based chemotherapy. The modified Glasgow prognostic score might be a predictor of SMI loss during treatment.

Huang, C.‐Y., Yang, Y.‐C., Chen, T.‐C., Chen, J.‐R., Chen, Y.‐J., Wu, M.‐H., Jan, Y.‐T., Chang, C.‐L., and Lee, J. ( 2020) Muscle loss during primary debulking surgery and chemotherapy predicts poor survival in advanced‐stage ovarian cancer, Journal of Cachexia, Sarcopenia and Muscle, 11, 534– 546. https://doi.org/10.1002/jcsm.12524.

ABSTRACT | PDF |

 

     Article first published online:  28 January 2020

Daniele Capitanio, Manuela Moriggi, Enrica Torretta, Pietro Barbacini, Sara De Palma, Agnese Viganò, Hanns Lochmüller, Francesco Muntoni, Alessandra Ferlini, Marina Mora, Cecilia Gelfi

Comparative proteomic analyses of Duchenne muscular dystrophy and Becker muscular dystrophy muscles:
changes contributing to preserve muscle function in Becker muscular dystrophy patients
Background
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are characterized by muscle wasting leading to loss of ambulation in the first or third decade, respectively. In DMD, the lack of dystrophin hampers connections between intracellular cytoskeleton and cell membrane leading to repeated cycles of necrosis and regeneration associated with inflammation and loss of muscle ordered structure. BMD has a similar muscle phenotype but milder. Here, we address the question whether proteins at variance in BMD compared with DMD contribute to the milder phenotype in BMD, thus identifying a specific signature to be targeted for DMD treatment.
Methods
Proteins extracted from skeletal muscle from DMD/BMD patients and young healthy subjects were either reduced and solubilized prior two‐dimensional difference in gel electrophoresis/mass spectrometry differential analysis or tryptic digested prior label‐free liquid chromatography with tandem mass spectrometry. Statistical analyses of proteins and peptides were performed by DeCyder and Perseus software and protein validation and verification by immunoblotting.
Results
Proteomic results indicate minor changes in the extracellular matrix (ECM) protein composition in BMD muscles with retention of mechanotransduction signalling, reduced changes in cytoskeletal and contractile proteins. Conversely, in DMD patients, increased levels of several ECM cytoskeletal and contractile proteins were observed whereas some proteins of fast fibres and of Z‐disc decreased. Detyrosinated alpha‐tubulin was unchanged in BMD and increased in DMD although neuronal nitric oxide synthase was unchanged in BMD and greatly reduced in DMD. Metabolically, the tissue is characterized by a decrement of anaerobic metabolism both in DMD and BMD compared with controls, with increased levels of the glycogen metabolic pathway in BMD. Oxidative metabolism is severely compromised in DMD with impairment of malate shuttle; conversely, it is active in BMD supporting the tricarboxylic acid cycle and respiratory chain. Adipogenesis characterizes DMD, whereas proteins involved in fatty acids beta‐oxidation are increased in BMD. Proteins involved in protein/amino acid metabolism, cell development, calcium handling, endoplasmic reticulum/sarcoplasmic reticulum stress response, and inflammation/immune response were increased in DMD. Both disorders are characterized by the impairment of N‐linked protein glycosylation in the endoplasmic reticulum. Authophagy was decreased in DMD whereas it was retained in BMD.
Conclusions
The mechanosensing and metabolic disruption are central nodes of DMD/BMD phenotypes. The ECM proteome composition and the metabolic rewiring in BMD lead to preservation of energy levels supporting autophagy and cell renewal, thus promoting the retention of muscle function. Conversely, DMD patients are characterized by extracellular and cytoskeletal protein dysregulation and by metabolic restriction at the level of α‐ketoglutarate leading to shortage of glutamate‐derived molecules that over time triggers lipogenesis and lipotoxicity.

Capitanio, D., Moriggi, M., Torretta, E., Barbacini, P., De Palma, S., Viganò, A., Lochmüller, H., Muntoni, F., Ferlini, A., Mora, M., and Gelfi, C. ( 2020) Comparative proteomic analyses of Duchenne muscular dystrophy and Becker muscular dystrophy muscles: changes contributing to preserve muscle function in Becker muscular dystrophy patients, Journal of Cachexia, Sarcopenia and Muscle, 11, 547– 563. https://doi.org/10.1002/jcsm.12527.

ABSTRACT | PDF |

 

     Article first published online:  28 January 2020

Jinyu Wang, Can Cui, Yu Ning Chim, Hao Yao, Liu Shi, Jiankun Xu, Jiali Wang, Ronald Man Yeung Wong, Kwok‐Sui Leung, Simon Kwoon‐Ho Chow, Wing Hoi Cheung

Vibration and β‐hydroxy‐β‐methylbutyrate treatment suppresses intramuscular fat infiltration and adipogenic differentiation in sarcopenic mice
Background
Sarcopenia is an aging‐induced deterioration of skeletal muscle mass and function. Low‐magnitude high‐frequency vibration (LMHFV) was shown to improve muscle functions and β‐hydroxy‐β‐methylbutyrate (HMB) to increase muscle mass and strength. Muscle‐derived stem cells (MDSCs) are progenitor cells important for muscle regeneration. We hypothesized that LMHFV and HMB could retard sarcopenia by reducing fat infiltration through inhibiting adipogenesis in MDSCs.
Methods
Senescence‐accelerated mouse P8 male mice were randomized into control (CTL), HMB, LMHFV (VIB), and combined (COM) groups. Interventions started at age of month 7 and assessed at 1, 2, and 3 months post‐intervention by densitometry, histology, and functional tests. In vitro, MDSCs isolated from gastrocnemius of senescence‐accelerated mouse P8 mice were characterized, randomized into CTL, VIB, HMB, and COM groups, and assessed by oil red O staining, mRNA, and protein expression.
Results
At 2 months post‐intervention, percentage lean mass of HMB, VIB, and COM groups were significantly higher than CTL group. Twitch, tetanic, and specific tetanic forces of COM group were higher, while specific twitch force of both VIB and COM groups were higher. Grip strength of HMB, VIB, and COM groups were higher. Histologically, both VIB and COM groups presented lower oil red O area than CTL group. Type I muscle fibre in CTL group was higher than HMB, VIB, and COM groups. MDSC were detected in situ by immunofluorescence stain with stem cell antigen‐1 signals confirmed with higher β‐catenin expression in the COM group. The observations were also confirmed in vitro, MDSCs in the HMB, VIB, and COM groups presented lower adipogenesis vs. the CTL group. β‐Catenin mRNA and protein expressions were lower in the CTL group while their relationship was further validated through β‐catenin knock‐down approach.
Conclusions
Our results showed that combined LMHFV and HMB interventions enhanced muscle strength and decreased percentage fat mass and intramuscular fat infiltration as compared with either treatment alone. Additive effect of LMHFV and HMB was demonstrated in β‐catenin expression than either treatment in MDSCs and altered cell fate from adipogenesis to myogenesis, leading to inhibition of intramuscular lipid accumulation. Wnt/β‐catenin signalling pathway was found to be the predominant regulatory mechanism through which LMHFV and HMB combined treatment suppressed MDSCs adipogenesis.

Wang, J., Cui, C., Chim, Y. N., Yao, H., Shi, L., Xu, J., Wang, J., Wong, R. M. Y., Leung, K.‐S., Chow, S. K.‐H., and Cheung, W. H. ( 2020) Vibration and β‐hydroxy‐β‐methylbutyrate treatment suppresses intramuscular fat infiltration and adipogenic differentiation in sarcopenic mice, Journal of Cachexia, Sarcopenia and Muscle, 11, 564– 577. https://doi.org/10.1002/jcsm.12535.

ABSTRACT | PDF |

 

     Article first published online:  17 December 2019

Tirsa L.E. van Westering, Yulia Lomonosova, Anna M.L. Coenen‐Stass, Corinne A. Betts, Amarjit Bhomra, Margriet Hulsker, Lucy E. Clark, Graham McClorey, Annemieke Aartsma‐Rus, Maaike van Putten, Matthew J.A. Wood, Thomas C. Roberts

Uniform sarcolemmal dystrophin expression is required to prevent extracellular microRNA release and improve dystrophic pathology
Background
Duchenne muscular dystrophy (DMD) is a fatal muscle‐wasting disorder caused by genetic loss of dystrophin protein. Extracellular microRNAs (ex‐miRNAs) are putative, minimally invasive biomarkers of DMD. Specific ex‐miRNAs (e.g. miR‐1, miR‐133a, miR‐206, and miR‐483) are highly up‐regulated in the serum of DMD patients and dystrophic animal models and are restored to wild‐type levels following exon skipping‐mediated dystrophin rescue in mdx mice. As such, ex‐miRNAs are promising pharmacodynamic biomarkers of exon skipping efficacy. Here, we aimed to determine the degree to which ex‐miRNA levels reflect the underlying level of dystrophin protein expression in dystrophic muscle.
Methods
Candidate ex‐miRNA biomarker levels were investigated in mdx mice in which dystrophin was restored with peptide‐PMO (PPMO) exon skipping conjugates and in mdx‐XistΔhs mice that express variable amounts of dystrophin from birth as a consequence of skewed X‐chromosome inactivation. miRNA profiling was performed in mdx‐XistΔhs mice using the FirePlex methodology and key results validated by small RNA TaqMan RT‐qPCR. The muscles from each animal model were further characterized by dystrophin western blot and immunofluorescence staining.
Results
The restoration of ex‐myomiR abundance observed following PPMO treatment was not recapitulated in the high dystrophin‐expressing mdx‐XistΔhs group, despite these animals expressing similar amounts of total dystrophin protein (~37% of wild‐type levels). Instead, ex‐miRNAs were present at high levels in mdx‐XistΔhs mice regardless of dystrophin expression. PPMO‐treated muscles exhibited a uniform pattern of dystrophin localization and were devoid of regenerating fibres, whereas mdx‐XistΔhs muscles showed non‐homogeneous dystrophin staining and sporadic regenerating foci.
Conclusions
Uniform dystrophin expression is required to prevent ex‐miRNA release, stabilize myofiber turnover, and attenuate pathology in dystrophic muscle.

van Westering, T. L. E., Lomonosova, Y., Coenen‐Stass, A. M. L., Betts, C. A., Bhomra, A., Hulsker, M., Clark, L. E., McClorey, G., Aartsma‐Rus, A., van Putten, M., Wood, M. J. A., and Roberts, T. C. ( 2020) Uniform sarcolemmal dystrophin expression is required to prevent extracellular microRNA release and improve dystrophic pathology, Journal of Cachexia, Sarcopenia and Muscle, 11, 578– 593. https://doi.org/10.1002/jcsm.12506.

ABSTRACT | PDF |

 

     Article first published online:  17 February 2020

Mareike S. Pötsch, Junichi Ishida, Sandra Palus, Anika Tschirner, Stephan von Haehling, Wolfram Doehner, Stefan D. Anker, Jochen Springer

MT‐102 prevents tissue wasting and improves survival in a rat model of severe cancer cachexia
Background
Cachexia, a common manifestation of malignant cancer, is associated with wasting of skeletal muscle and fat tissue. In this study, we investigated the effects of a new first in class anabolic catabolic transforming agent on skeletal muscle in a rat model of cancer cachexia.
Methods
Young male Wistar Han rats were intraperitoneally inoculated with 108 Yoshida hepatoma AH‐130 cells and once daily treated with 0.3 mg kg−1, 3 mg kg−1 MT‐102, or placebo by gavage.
Results
Three mg kg−1d−1 MT‐102 not only prevented progressive loss of fat mass (−6 ± 2 g vs ‐12 ± 1 g; P < 0.001); lean mass (+1 ± 10 g vs. −37 ± 2 g; P < 0.001) and body weight (+1 ± 13 g vs. −60 ± 2 g; P < 0.001) were remained. Quality of life was also improved as indicated by a higher food intake 12.9 ± 3.1 g and 4.3 ± 0.5 g, 3 mg kg−1d−1 MT‐102 vs. placebo, respectively, P < 0.001) and a higher spontaneous activity (52 369 ± 6521 counts/24 h and 29 509 ± 1775 counts/24 h, 3 mg·kg‐1d‐1 MT‐102 vs. placebo, respectively, P < 0.01) on Day 11. Most importantly, survival was improved (HR = 0.29; 95% CI: 0.16–0.51, P < 0.001). The molecular mechanisms behind these effects involve reduction of overall protein degradation and activation of protein synthesis, assessed by measurement of proteasome and caspase‐6 activity or Western blot analysis, respectively.
Conclusions
The present study shows that 3 mg kg−1 MT‐102 reduces catabolism, while inducing anabolism in skeletal muscle leading to an improved survival.

Pötsch, M. S., Ishida, J., Palus, S., Tschirner, A., von Haehling, S., Döhner, W., Anker, S. D., and Springer, J. ( 2020) MT‐102 prevents tissue wasting and improves survival in a rat model of severe cancer cachexia, Journal of Cachexia, Sarcopenia and Muscle, 11, 594– 605. https://doi.org/10.1002/jcsm.12537.

ABSTRACT | PDF |