Prolonged Immobilization Exacerbates the Loss of Muscle Mass and Function Induced by Cancer-Associated Cachexia through Enhanced Proteolysis in Mice

We hypothesized that in mice with lung cancer (LC)-induced cachexia, periods of immobilization of the hindlimb (7 and 15 days) may further aggravate the process of muscle mass loss and function. Mice were divided into seven groups (n = 10/group): (1) non-immobilized control mice, (2) 7-day unloaded mice (7-day I), (3) 15-day unloaded mice (15-day I), (4) 21-day LC-cachexia group (LC 21-days), (5) 30-day LC-cachexia group (LC 30-days), (6) 21-day LC-cachexia group besides 7 days of unloading (LC 21-days + 7-day I), (7) 30-day LC-cachexia group besides 15 days of unloading (LC 30-days + 15-day I). Physiological parameters, body weight, muscle and tumor weights, phenotype and morphometry, muscle damage (including troponin I), proteolytic and autophagy markers, and muscle regeneration markers were identified in gastrocnemius muscle. In LC-induced cachexia mice exposed to hindlimb unloading, gastrocnemius weight, limb strength, fast-twitch myofiber cross-sectional area, and muscle regeneration markers significantly decreased, while tumor weight and area, muscle damage (troponin), and proteolytic and autophagy markers increased. In gastrocnemius of cancer-cachectic mice exposed to unloading, severe muscle atrophy and impaired function was observed along with increased muscle proteolysis and autophagy, muscle damage, and impaired muscle regeneration.

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Skeletal muscle response to spaceflight, whole body suspension, and recovery in rats

Journal of Applied Physiology ◽

10.1152/jappl.1990.69.6.2248 ◽

1990 ◽

Vol 69 (6) ◽

pp. 2248-2253 ◽

Cited By ~ 53

Author(s):

X. J. Musacchia ◽

J. M. Steffen ◽

R. D. Fell ◽

M. J. Dombrowski

Keyword(s):

Muscle Mass ◽

Muscle Metabolism ◽

Capillary Density ◽

Whole Body ◽

Sprague Dawley ◽

Cross Sectional ◽

Muscle Plasticity ◽

Sprague Dawley Rats ◽

Muscle Mass Loss ◽

Fast Twitch

Comparisons of soleus and extensor digitorum longus (EDL) muscles from male Sprague-Dawley rats (350-400 g) after 7 days of weightlessness, 7 and 14 days of whole body suspension (WBS), and 7 days of recovery from WBS and from vivarium controls were made. Muscle mass loss of approximately 30% was observed in soleus after 7 and 14 days of WBS. Measurement of slow- and fast-twitch fibers showed significant alterations. Reductions in cross-sectional areas and increases in fiber densities in soleus after spaceflight and WBS were related to previous findings of muscle atrophy during unloading. Capillary density also showed a marked increase with unloading. Seven days of weightlessness were sufficient to effect a 20 and 15% loss in absolute muscle mass in soleus and EDL, respectively. However, the antigravity soleus was more responsive in terms of cross-sectional area reductions. After 7 days of recovery from WBS, with normal ambulatory loading, the parameters studied showed a reversal to control levels. Muscle plasticity, in terms of fiber and capillary responses, indicated differences in responses in the two types of muscles and further amplified that antigravity posture muscles are highly susceptible to unloading. Studies of recovery from spaceflight for both muscle metabolism and microvascular modifications are further justified.

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Obesity-induced discrepancy between contractile and metabolic phenotypes in slow- and fast-twitch skeletal muscles of female obese Zucker rats

Journal of Applied Physiology ◽

10.1152/japplphysiol.00282.2017 ◽

2017 ◽

Vol 123 (1) ◽

pp. 249-259 ◽

Cited By ~ 7

Author(s):

Luz M. Acevedo ◽

Ana I. Raya ◽

Rafael Ríos ◽

Escolástico Aguilera-Tejero ◽

José-Luis L. Rivero

Keyword(s):

Muscle Mass ◽

Skeletal Muscles ◽

Fiber Type ◽

Succinic Dehydrogenase ◽

Zucker Rats ◽

Fiber Types ◽

Type Composition ◽

Obese Zucker Rats ◽

And Function ◽

Fast Twitch

A clear picture of skeletal muscle adaptations to obesity and related comorbidities remains elusive. This study describes fiber-type characteristics (size, proportions, and oxidative enzyme activity) in two typical hindlimb muscles with opposite structure and function in an animal model of genetic obesity. Lesser fiber diameter, fiber-type composition, and histochemical succinic dehydrogenase activity (an oxidative marker) of muscle fiber types were assessed in slow (soleus)- and fast (tibialis cranialis)-twitch muscles of obese Zucker rats and compared with age (16 wk)- and sex (females)-matched lean Zucker rats ( n = 16/group). Muscle mass and lesser fiber diameter were lower in both muscle types of obese compared with lean animals even though body weights were increased in the obese cohort. A faster fiber-type phenotype also occurred in slow- and fast-twitch muscles of obese rats compared with lean rats. These adaptations were accompanied by a significant increment in histochemical succinic dehydrogenase activity of slow-twitch fibers in the soleus muscle and fast-twitch fiber types in the tibialis cranialis muscle. Obesity significantly increased plasma levels of proinflammatory cytokines but did not significantly affect protein levels of peroxisome proliferator-activated receptors PPARγ or PGC1α in either muscle. These data demonstrate that, in female Zucker rats, obesity induces a reduction of muscle mass in which skeletal muscles show a diminished fiber size and a faster and more oxidative phenotype. It was noteworthy that this discrepancy in muscle's contractile and metabolic features was of comparable nature and extent in muscles with different fiber-type composition and antagonist functions. NEW & NOTEWORTHY This study demonstrates a discrepancy between morphological (reduced muscle mass), contractile (shift toward a faster phenotype), and metabolic (increased mitochondrial oxidative enzyme activity) characteristics in skeletal muscles of female Zucker fatty rats. It is noteworthy that this inconsistency was comparable (in nature and extent) in muscles with different structure and function.

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Beneficial Effects of Resveratrol in Mouse Gastrocnemius: A Hint to Muscle Phenotype and Proteolysis

Cells ◽

10.3390/cells10092436 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2436

Author(s):

Laura Mañas-García ◽

Charlotte Denhard ◽

Javier Mateu ◽

Xavier Duran ◽

Joaquim Gea ◽

...

Keyword(s):

Signaling Pathways ◽

Muscle Fiber ◽

Troponin I ◽

Muscle Protein ◽

Strength Loss ◽

Muscle Weight ◽

Cross Sectional ◽

Therapeutic Implications ◽

Resveratrol Treatment ◽

And Function

We hypothesized that the phenolic compound resveratrol mitigates muscle protein degradation and loss and improves muscle fiber cross-sectional area (CSA) in gastrocnemius of mice exposed to unloading (7dI). In gastrocnemius of mice (female C57BL/6J, 10 weeks) exposed to a seven-day period of hindlimb immobilization with/without resveratrol treatment, markers of muscle proteolysis (tyrosine release, systemic troponin-I), atrophy signaling pathways, and muscle phenotypic features and function were analyzed. In gastrocnemius of unloaded mice treated with resveratrol, body and muscle weight and function were attenuated, whereas muscle proteolysis (tyrosine release), proteolytic and apoptotic markers, atrophy signaling pathways, and myofiber CSA significantly improved. Resveratrol treatment of mice exposed to a seven-day period of unloading prevented body and muscle weight and limb strength loss, while an improvement in muscle proteolysis, proteolytic markers, atrophy signaling pathways, apoptosis, and muscle fiber CSA was observed in the gastrocnemius muscle. These findings may have potential therapeutic implications in the management of disuse muscle atrophy in clinical settings.

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P1586SARCOPENIA IN HEMODIALYSIS PATIENTS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1586 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Armando Luis Negri ◽

Ruben Abdala ◽

Elisa Del Valle ◽

Pablo Bridoux ◽

Luciana Gonzalez Paganti ◽

...

Keyword(s):

Grip Strength ◽

Muscle Mass ◽

Physical Performance ◽

Significant Proportion ◽

Cross Sectional Study ◽

Dialysis Patients ◽

Cross Sectional ◽

Hand Grip ◽

Hand Dynamometer ◽

And Function

Abstract Background and Aims Sarcopenia is the loss of skeletal muscle mass and function that occurs with aging. These modifications lead to greater morbidity and mortality as a result of falls, hospitalization, depression and dependence among others. Chronic Kidney disease (CKD) and hemodialysis (HD) produce a favorable environment for the development of sarcopenia. Objective: to study the prevalence of sarcopenia and its different components (muscle mass, strength and physical performance) using EWGSOP 2018 proposed criteria. Method cross-sectional study evaluating 100 adult HD patients. We evaluated: Grip strength (GS) with Jamar Hydraulic Hand Dynamometer (three determinations in the arm without fistula); Appendicular lean mass (ALM) by DXA (GE LUNAR Prodigy Advance) and physical performance: Gait-speed (Time needed to perform a 4-meter walk on a flat surface) and the sit-stand test Results 58 males (M) and 42 females (F). Mean age for M was 54.3 years and 58 years for F. The prevalence of sarcopenia was 18% in the whole group, 10% in M and 20% in F. In M 33% had low GS and 26% low ALM. In M GS correlated with ALM, Albumin and weight p<0.05 (R 2 0.41); ALM correlated with weight r 0.75, height r 0.64 and GS r 0.46 (p<0.05). In F, 27% had low GS, 54% low ALM, and 17% poor physical performance. In F, GS correlated positively with ALM; ALM correlated positively with: weight r 0.78, height r 0.66, GS r 0.59 and sit-stand r 0.40 (p<0.5). Patients with lower grip strength had a higher prevalence of falls in the last year (40% two or more falls) p=0.03. Conclusion A significant proportion of dialysis patients had sarcopenia. Low hand grip strength was associated with a higher prevalence of falls. Recognizing sarcopenia in dialysis patients would allow us to develop strategies to prevent falls and other complications.

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Role(s) of nucleoli and phosphorylation of ribosomal protein S6 and/or HSP27 in the regulation of muscle mass

AJP Cell Physiology ◽

10.1152/ajpcell.00297.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. C35-C44 ◽

Cited By ~ 44

Author(s):

F. Kawano ◽

Y. Matsuoka ◽

Y. Oke ◽

Y. Higo ◽

M. Terada ◽

...

Keyword(s):

Ribosomal Protein ◽

Muscle Mass ◽

Mechanical Load ◽

Domain Size ◽

Hindlimb Unloading ◽

Cross Sectional ◽

Ribosomal Protein S6 ◽

Myonuclear Domain ◽

Nucleolar Number ◽

Integrated Electromyogram

Effects of 14 days of hindlimb unloading or synergist ablation-related overloading with or without deafferentation on the fiber cross-sectional area, myonuclear number, size, and domain, the number of nucleoli in a single myonucleus, and the levels in the phosphorylation of the ribosomal protein S6 (S6) and 27-kDa heat shock protein (HSP27) were studied in rat soleus. Hypertrophy of fibers (+24%), associated with increased nucleolar number (from 1–2 to 3–5) within a myonucleus and myonuclear domain (+27%) compared with the preexperimental level, was induced by synergist ablation. Such phenomena were associated with increased levels of phosphorylated S6 (+84%) and HSP27 (+28%). Fiber atrophy (−52%), associated with decreased number (−31%) and domain size (−28%) of myonuclei and phosphorylation of S6 (−98%) and HSP27 (−63%), and with increased myonuclear size (+19%) and ubiquitination of myosin heavy chain (+33%, P > 0.05), was observed after unloading, which inhibited the mechanical load. Responses to deafferentation, which inhibited electromyogram level (−47%), were basically similar to those caused by hindlimb unloading, although the magnitudes were minor. The deafferentation-related responses were prevented and nucleolar number was even increased (+18%) by addition of synergist ablation, even though the integrated electromyogram level was still 30% less than controls. It is suggested that the load-dependent maintenance or upregulation of the nucleolar number and/or phosphorylation of S6 and HSP27 plays the important role(s) in the regulation of muscle mass. It was also indicated that such regulation was not necessarily associated with the neural activity.

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Fast skeletal troponin I, but not the slow isoform, is increased in patients under statin therapy: a pilot study

Biochemia Medica ◽

10.11613/bm.2019.010703 ◽

2018 ◽

Vol 29 (1) ◽

pp. 68-76

Author(s):

Alessandro Trentini ◽

Maria C Manfrinato ◽

Tiziana Bellini ◽

Carlo A Volta ◽

Stefania Hanau ◽

...

Keyword(s):

Skeletal Muscle ◽

Creatine Kinase ◽

Statin Therapy ◽

Muscle Damage ◽

Troponin I ◽

Academic Hospital ◽

Creatine Kinase Mb ◽

The University ◽

Fast Twitch ◽

Muscular Damage

Introduction: Statin therapy is often associated with muscle complaints and increased serum creatine kinase (CK). However, although essential in determining muscle damage, this marker is not specific for skeletal muscle. Recent studies on animal models have shown that slow and fast isoforms of skeletal troponin I (ssTnI and fsTnI, respectively) can be useful markers of skeletal muscle injury. The aim of this study was to evaluate the utility of ssTnI and fsTnI as markers to monitor the statin-induced skeletal muscle damage. Materials and methods: A total of 51 patients (14 using and 37 not using statins) admitted to the intensive care unit of the University of Ferrara Academic Hospital were included in this observational study. Serum activities of CK, aldolase, alanine aminotransferase and myoglobin were determined by spectrophotometric assays or routine laboratory analysis. Isoforms ssTnI and fsTnI were determined by commercially available ELISAs. The creatine kinase MB isoform (CK-MB) and cardiac troponin I (cTnI) were evaluated as biomarkers of cardiac muscle damage by automatic analysers. Results: Among the non-specific markers, only CK was significantly higher in statin users (P = 0.027). Isoform fsTnI, but not ssTnI, was specifically increased in those patients using statins (P = 0.009) evidencing the major susceptibility of fast-twitch fibres towards statins. Sub-clinical increase in fsTnI, but not CK, was more frequent in statin users (P = 0.007). Cardiac markers were not significantly altered by statins confirming the selectivity of the effect on skeletal muscle. Conclusions: Serum fsTnI could be a good marker for monitoring statin-associated muscular damage outperforming traditional markers.

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Early functional muscle regeneration after myotoxic injury in mice is unaffected by nNOS absence

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00096.2011 ◽

2011 ◽

Vol 301 (5) ◽

pp. R1358-R1366 ◽

Cited By ~ 10

Author(s):

Jarrod E. Church ◽

Stefan M. Gehrig ◽

Annabel Chee ◽

Timur Naim ◽

Jennifer Trieu ◽

...

Keyword(s):

Muscle Regeneration ◽

Cross Sectional Area ◽

No Production ◽

Sectional Area ◽

Wild Type ◽

Wild Type Littermate ◽

Cross Sectional ◽

Neuronal Subtype ◽

Genetic Deletion ◽

And Function

Nitric oxide (NO) is an important signaling molecule produced in skeletal muscle primarily via the neuronal subtype of NO synthase (NOS1, or nNOS). While many studies have reported NO production to be important in muscle regeneration, none have examined the contribution of nNOS-derived NO to functional muscle regeneration (i.e., restoration of the muscle's ability to produce force) after acute myotoxic injury. In the present study, we tested the hypothesis that genetic deletion of nNOS would impair functional muscle regeneration after myotoxic injury in nNOS−/− mice. We found that nNOS−/− mice had lower body mass, lower muscle mass, and smaller myofiber cross-sectional area and that their tibialis anterior (TA) muscles produced lower absolute tetanic forces than those of wild-type littermate controls but that normalized or specific force was identical between the strains. In addition, muscles from nNOS−/− mice were more resistant to fatigue than those of wild-type littermates ( P < 0.05). To determine whether deletion of nNOS affected muscle regeneration, TA muscles from nNOS−/− mice and wild-type littermates were injected with the myotoxin notexin to cause complete fiber degeneration, and muscle structure and function were assessed at 7 and 10 days postinjury. Myofiber cross-sectional area was lower in regenerating nNOS−/− mice than wild-type controls at 7 and 10 days postinjury; however, contrary to our original hypothesis, no difference in force-producing capacity of the TA muscle was evident between the two groups at either time point. Our findings reveal that nNOS is not essential for functional muscle regeneration after acute myotoxic damage.

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Gut Microbiota, Muscle Mass and Function in Aging: A Focus on Physical Frailty and Sarcopenia

Nutrients ◽

10.3390/nu11071633 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1633 ◽

Cited By ~ 36

Author(s):

Andrea Ticinesi ◽

Antonio Nouvenne ◽

Nicoletta Cerundolo ◽

Pamela Catania ◽

Beatrice Prati ◽

...

Keyword(s):

Gut Microbiota ◽

Physical Function ◽

Muscle Mass ◽

Physical Performance ◽

Microbiota Composition ◽

Physical Frailty ◽

Deficit Accumulation ◽

Cross Sectional ◽

Age Related ◽

And Function

Human gut microbiota is able to influence the host physiology by regulating multiple processes, including nutrient absorption, inflammation, oxidative stress, immune function, and anabolic balance. Aging is associated with reduced microbiota biodiversity, increased inter-individual variability, and over-representation of pathobionts, and these phenomena may have great relevance for skeletal muscle mass and function. For this reason, the presence of a gut-muscle axis regulating the onset and progression of age-related physical frailty and sarcopenia has been recently hypothesized. In this narrative review, we summarize the studies supporting a possible association between gut microbiota-related parameters with measures of muscle mass, muscle function, and physical performance in animal models and humans. Reduced muscle mass has been associated with distinct microbiota composition and reduced fermentative capacity in mice, and the administration of probiotics or butyrate to mouse models of muscle wasting has been associated with improved muscle mass. However, no studies have targeted the human microbiome associated with sarcopenia. Limited evidence from human studies shows an association between microbiota composition, involving key taxa such as Faecalibacterium and Bifidobacterium, and grip strength. Similarly, few studies conducted on patients with parkinsonism showed a trend towards a different microbiota composition in those with reduced gait speed. No studies have assessed the association of fecal microbiota with other measures of physical performance. However, several studies, mainly with a cross-sectional design, suggest an association between microbiota composition and frailty, mostly assessed according to the deficit accumulation model. Namely, frailty was associated with reduced microbiota biodiversity, and lower representation of butyrate-producing bacteria. Therefore, we conclude that the causal link between microbiota and physical fitness is still uncertain due to the lack of targeted studies and the influence of a large number of covariates, including diet, exercise, multimorbidity, and polypharmacy, on both microbiota composition and physical function in older age. However, the relationship between gut microbiota and physical function remains a very promising area of research for the future.

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Effects of lower limb unloading on skeletal muscle mass and function in humans

Journal of Applied Physiology ◽

10.1152/jappl.1991.70.4.1882 ◽

1991 ◽

Vol 70 (4) ◽

pp. 1882-1885 ◽

Cited By ~ 136

Author(s):

H. E. Berg ◽

G. A. Dudley ◽

T. Haggmark ◽

H. Ohlsen ◽

P. A. Tesch

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Lower Limb ◽

Skeletal Muscle Mass ◽

Bed Rest ◽

Experimental Period ◽

Peak Torque ◽

Human Model ◽

Cross Sectional ◽

And Function

A model to simulate effects of microgravity on skeletal muscle mass and function in humans has been developed. Unilateral lower limb unloading that allowed ankle, knee, and hip joint mobility was conducted in six healthy men by suspending one lower limb and having the subjects walk on crutches. They performed maximal unilateral concentric or eccentric quadriceps actions at different angular velocities before and after 4 wk of suspension and after 4 days and after 7 wk of uncontrolled recovery. Peak torque (PT) and angle-specific torque (AST) were measured. Muscle cross-sectional area (CSA) and radiological density (RD) of the thigh were assessed by means of computerized tomography. Concentric and eccentric PT and AST across speeds decreased (P less than 0.05) by 22 and 16%, respectively, in response to unloading. At 4 days of recovery PT (-11%) and AST (-7%) were still lower (P less than 0.05) than before. Muscle CSA and RD decreased (P less than 0.05) by 7 and 6%, respectively. After 7 wk of recovery PT, AST, CSA, and RD had returned to normal. The control limb showed no changes over the experimental period except for a 6% decrease (P less than 0.05) in RD. It is suggested that this human model of unloading could serve to simulate effects of microgravity on skeletal muscle mass and function because reductions in muscle mass and strength were of similar magnitude to those produced by bed rest.

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Nutrient-dense protein as a primary dietary strategy in healthy ageing: please sir, may we have more?

Proceedings of The Nutrition Society ◽

10.1017/s0029665120007892 ◽

2020 ◽

pp. 1-14

Author(s):

E. A. Nunes ◽

B. S. Currier ◽

C. Lim ◽

S. M. Phillips

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Dietary Protein ◽

Muscle Function ◽

Protein Quality ◽

Dietary Quality ◽

Current Evidence ◽

Protein Ingestion ◽

Muscle Mass Loss ◽

And Function

A progressive decrement in muscle mass and muscle function, sarcopoenia, accompanies ageing. The loss of skeletal muscle mass and function is the main feature of sarcopoenia. Preventing the loss of muscle mass is relevant since sarcopoenia can have a significant impact on mobility and the quality of life of older people. Dietary protein and physical activity have an essential role in slowing muscle mass loss and helping to maintain muscle function. However, the current recommendations for daily protein ingestion for older persons appear to be too low and are in need of adjustment. In this review, we discuss the skeletal muscle response to protein ingestion, and review the data examining current dietary protein recommendations in the older subjects. Furthermore, we review the concept of protein quality and the important role that nutrient-dense protein (NDP) sources play in meeting overall nutrient requirements and improving dietary quality. Overall, the current evidence endorses an increase in the daily ingestion of protein with emphasis on the ingestion of NDP choices by older adults.

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