Testosterone Supplementation Reverses Sarcopenia in Aging through Regulation of Myostatin, c-Jun NH2-Terminal Kinase, Notch, and Akt Signaling Pathways

Aging in rodents and humans is characterized by loss of muscle mass (sarcopenia). Testosterone supplementation increases muscle mass in healthy older men. Here, using a mouse model, we investigated the molecular mechanisms by which testosterone prevents sarcopenia and promotes muscle growth in aging. Aged mice of 22 months of age received a single sc injection of GnRH antagonist every 2 wk to suppress endogenous testosterone production and were implanted subdermally under anesthesia with 0.5 or 1.0 cm testosterone-filled implants for 2 months (n = 15/group). Young and old mice (n = 15/group), of 2 and 22 months of age, respectively, received empty implants and were used as controls. Compared with young animals, a significant (P < 0.05) increase in muscle cell apoptosis coupled with a decrease in gastrocnemius muscles weight (by 16.7%) and muscle fiber cross-sectional area, of both fast and slow fiber types, was noted in old mice. Importantly, such age-related changes were fully reversed by higher dose (1 cm) of testosterone treatment. Testosterone treatment effectively suppressed age-specific increases in oxidative stress, processed myostatin levels, activation of c-Jun NH2-terminal kinase, and cyclin-dependent kinase inhibitor p21 in aged muscles. Furthermore, it restored age-related decreases in glucose-6-phosphate dehydrogenase levels, phospho-Akt, and Notch signaling. These alterations were associated with satellite cell proliferation and differentiation. Collectively these results suggest involvement of multiple signal transduction pathways in sarcopenia. Testosterone reverses sarcopenia through stimulation of cellular metabolism and survival pathway together with inhibition of death pathway.

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Physiology of a Microgravity Environment Invited Review: Microgravity and skeletal muscle

Journal of Applied Physiology ◽

10.1152/jappl.2000.89.2.823 ◽

2000 ◽

Vol 89 (2) ◽

pp. 823-839 ◽

Cited By ~ 332

Author(s):

Robert H. Fitts ◽

Danny R. Riley ◽

Jeffrey J. Widrick

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Thin Filament ◽

Molecular Mechanisms ◽

Skeletal Muscle Atrophy ◽

Microgravity Environment ◽

Type I ◽

Fiber Types ◽

Maximal Velocity ◽

Cross Sectional

Spaceflight (SF) has been shown to cause skeletal muscle atrophy; a loss in force and power; and, in the first few weeks, a preferential atrophy of extensors over flexors. The atrophy primarily results from a reduced protein synthesis that is likely triggered by the removal of the antigravity load. Contractile proteins are lost out of proportion to other cellular proteins, and the actin thin filament is lost disproportionately to the myosin thick filament. The decline in contractile protein explains the decrease in force per cross-sectional area, whereas the thin-filament loss may explain the observed postflight increase in the maximal velocity of shortening in the type I and IIa fiber types. Importantly, the microgravity-induced decline in peak power is partially offset by the increased fiber velocity. Muscle velocity is further increased by the microgravity-induced expression of fast-type myosin isozymes in slow fibers (hybrid I/II fibers) and by the increased expression of fast type II fiber types. SF increases the susceptibility of skeletal muscle to damage, with the actual damage elicited during postflight reloading. Evidence in rats indicates that SF increases fatigability and reduces the capacity for fat oxidation in skeletal muscles. Future studies will be required to establish the cellular and molecular mechanisms of the SF-induced muscle atrophy and functional loss and to develop effective exercise countermeasures.

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Muscle growth, cell number, type and morphometry in single and twin fetal lambs during mid to late gestation

Reproduction Fertility and Development ◽

10.1071/rd99059 ◽

2000 ◽

Vol 12 (6) ◽

pp. 319 ◽

Cited By ~ 28

Author(s):

S. A. McCoard ◽

W. C. McNabb ◽

S. W. Peterson ◽

S. N. McCutcheon ◽

P. M. Harris

Keyword(s):

Muscle Mass ◽

Litter Size ◽

Muscle Growth ◽

Cell Number ◽

Late Gestation ◽

Postnatal Life ◽

Cross Sectional ◽

Hindlimb Muscles ◽

Full Complement ◽

Gastrocnemius Muscles

Muscle growth, myofibre number, type and morphometry were studied in large hindlimb muscles of single and twin fetal lambs during mid to late gestation. Placental insufficiency, evident by lower total placentome weight and number per fetus, resulted in reduced fetal weights from 100 to 140 days gestation in twins compared with singletons (at 140 days: 5016 108 g v. 5750 246 g, respectively; P<0.05). However, competition between littermates did not consistently reduce muscle mass (15–22%) until 140 days gestation. Apparent myofibre number increased with age, indicating that the full complement of myofibres in some large hindlimb muscles may be achieved during early postnatal life. Litter size did not impact on apparent myofibre number in the semitendinosus, plantaris or gastrocnemius muscles. However, a transient effect on myofibre number in the adductor femoris muscle was observed from 80–120 days gestation. The phenotypic maturation of myofibres was unaffected by increasing litter size. Smaller muscle mass in twins was associated with smaller myofibre cross-sectional area in the semitendinosus, adductor femoris and gastrocnemius muscles at 140 days gestation. A similar trend was observed for the plantaris muscle. These results indicate that while competition between littermates for nutrients in late gestation can impact on both fetal and muscle mass, the fetus has the capacity to buffer against the effects of restricted nutrient supply on myofibre hyperplasia and phenotypic maturation, but myofibre hypertrophy is compromised.

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The Effects of Aging and Training on Skeletal Muscle

The American Journal of Sports Medicine ◽

10.1177/03635465980260042401 ◽

1998 ◽

Vol 26 (4) ◽

pp. 598-602 ◽

Cited By ~ 130

Author(s):

Donald T. Kirkendall ◽

William E. Garrett

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Muscle Function ◽

Cellular Level ◽

Type I ◽

Loss Of Function ◽

Skeletal Muscle Function ◽

Cross Sectional ◽

Age Related ◽

General Slowing

Aging results in a gradual loss of muscle function, and there are predictable age-related alterations in skeletal muscle function. The typical adult will lose muscle mass with age; the loss varies according to sex and the level of muscle activity. At the cellular level, muscles loose both cross-sectional area and fiber numbers, with type II muscle fibers being the most affected by aging. Some denervation of fibers may occur. The combination of these factors leads to an increased percentage of type I fibers in older adults. Metabolically, the glycolytic enzymes seem to be little affected by aging, but the aerobic enzymes appear to decline with age. Aged skeletal muscle produces less force and there is a general “slowing” of the mechanical characteristics of muscle. However, neither reduced muscle demand nor the subsequent loss of function is inevitable with aging. These losses can be minimized or even reversed with training. Endurance training can improve the aerobic capacity of muscle, and resistance training can improve central nervous system recruitment of muscle and increase muscle mass. Therefore, physical activity throughout life is encouraged to prevent much of the age-related impact on skeletal muscle.

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The Relationship Between Intermuscular Fat and Physical Performance Is Moderated by Muscle Area in Older Adults

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa161 ◽

2020 ◽

Vol 76 (1) ◽

pp. 115-122

Author(s):

Samaneh Farsijani ◽

Adam J Santanasto ◽

Iva Miljkovic ◽

Robert M Boudreau ◽

Bret H Goodpaster ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Physical Performance ◽

Functional Limitations ◽

Negative Association ◽

Muscle Area ◽

Cross Sectional ◽

Age Related ◽

Intermuscular Fat ◽

The Mean

Abstract Background Age-related deposition of fat in skeletal muscle is associated with functional limitations. Skeletal muscle fat may be present in people with preserved muscle mass or accompanied by muscle wasting. However, it is not clear if the association between muscle fat deposition and physical performance is moderated by muscle mass. Objective To determine whether the association between midthigh intermuscular fat and physical performance is moderated by muscle area. Methods We performed a cross-sectional analysis of the Health, Aging, and, Body Composition (ABC) study data collected in 2002–2003 (n = 1897, women: 52.2%). Midthigh muscle cross-sectional area (by computed tomography) and physical performance measures were compared across quartiles of intermuscular fat absolute area. Moderation analysis was performed to determine the conditional effect of intermuscular fat on physical performance as a function of muscle area. Conditional effects were evaluated at three levels of muscle area (mean and ± 1 standard deviation [SD]; 213.2 ± 53.2 cm2). Results Simple slope analysis showed that the negative association between intermuscular fat area (cm2) and leg strength (N·m) was of greater magnitude (beta coefficient [b], 95% confidence interval [CI] = −0.288 [−0.427, −0.148]) in participants with greater muscle area (ie, 1 SD above the mean) compared to those with lower muscle area (ie, at mean [b = −0.12 {−0.248, 0.008}] or 1 SD below the mean [b = 0.048 {−0.122, 0.217}]). Similarly, the negative association of intermuscular fat with 400-m walk speed (m/s) and chair stand (seconds) was greater in those with higher muscle areas (p < .001) compared to those with lower muscle areas. Conclusions The association between higher intermuscular fat area and impaired physical function in aging is moderated by muscle area.

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Automated rodent in situ muscle contraction assay and myofiber organization analysis in sarcopenia animal models

Journal of Applied Physiology ◽

10.1152/japplphysiol.00871.2011 ◽

2012 ◽

Vol 112 (12) ◽

pp. 2087-2098 ◽

Cited By ~ 10

Author(s):

H. Weber ◽

A. Rauch ◽

S. Adamski ◽

K. Chakravarthy ◽

A. Kulkarni ◽

...

Keyword(s):

Muscle Mass ◽

Force Measurement ◽

Muscle Performance ◽

Area Measurement ◽

Micro Ct ◽

Cross Sectional ◽

Muscle Aging ◽

Age Related

Age-related sarcopenia results in frailty and decreased mobility, which are associated with increased falls and long-term disability in the elderly. Given the global increase in lifespan, sarcopenia is a growing, unmet medical need. This report aims to systematically characterize muscle aging in preclinical models, which may facilitate the development of sarcopenia therapies. Naïve rats and mice were subjected to noninvasive micro X-ray computed tomography (micro-CT) imaging, terminal in situ muscle function characterizations, and ATPase-based myofiber analysis. We developed a Definiens (Parsippany, NJ)-based algorithm to automate micro-CT image analysis, which facilitates longitudinal in vivo muscle mass analysis. We report development and characterization of translational in situ skeletal muscle performance assay systems in rat and mouse. The systems incorporate a custom-designed animal assay stage, resulting in enhanced force measurement precision, and LabVIEW (National Instruments, Austin, TX)-based algorithms to support automated data acquisition and data analysis. We used ATPase-staining techniques for myofibers to characterize fiber subtypes and distribution. Major parameters contributing to muscle performance were identified using data mining and integration, enabled by Labmatrix (BioFortis, Columbia, MD). These technologies enabled the systemic and accurate monitoring of muscle aging from a large number of animals. The data indicated that longitudinal muscle cross-sectional area measurement effectively monitors change of muscle mass and function during aging. Furthermore, the data showed that muscle performance during aging is also modulated by myofiber remodeling factors, such as changes in myofiber distribution patterns and changes in fiber shape, which affect myofiber interaction. This in vivo muscle assay platform has been applied to support identification and validation of novel targets for the treatment of sarcopenia.

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FTIR Spectroscopy as a Tool to Study Age-Related Changes in Cardiac and Skeletal Muscle of Female C57BL/6J Mice

Molecules ◽

10.3390/molecules26216410 ◽

2021 ◽

Vol 26 (21) ◽

pp. 6410

Author(s):

Sandra Magalhães ◽

Idália Almeida ◽

Filipa Martins ◽

Fátima Camões ◽

Ana R. Soares ◽

...

Keyword(s):

Skeletal Muscle ◽

Ftir Spectroscopy ◽

Conformational Changes ◽

Molecular Mechanisms ◽

Protein Secondary Structure ◽

Multivariate Statistical ◽

Age Related ◽

Muscle Tissues ◽

Aging Studies ◽

Old Mice

Studying aging is important to further understand the molecular mechanisms underlying this physiological process and, ideally, to identify a panel of aging biomarkers. Animals, in particular mice, are often used in aging studies, since they mimic important features of human aging, age quickly, and are easy to manipulate. The present work describes the use of Fourier Transform Infrared (FTIR) spectroscopy to identify an age-related spectroscopic profile of the cardiac and skeletal muscle tissues of C57BL/6J female mice. We acquired ATR-FTIR spectra of cardiac and skeletal muscle at four different ages: 6; 12; 17 and 24 months (10 samples at each age) and analyzed the data using multivariate statistical tools (PCA and PLS) and peak intensity analyses. The results suggest deep changes in protein secondary structure in 24-month-old mice compared to both tissues in 6-month-old mice. Oligomeric structures decreased with age in both tissues, while intermolecular β-sheet structures increased with aging in cardiac muscle but not in skeletal muscle. Despite FTIR spectroscopy being unable to identify the proteins responsible for these conformational changes, this study gives insights into the potential of FTIR to monitor the aging process and identify an age-specific spectroscopic signature.

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Influence of varying degrees of malnutrition on IGF-I expression in the rat diaphragm

Journal of Applied Physiology ◽

10.1152/japplphysiol.00916.2002 ◽

2003 ◽

Vol 95 (2) ◽

pp. 555-562 ◽

Cited By ~ 17

Author(s):

Michael I. Lewis ◽

Hongyan Li ◽

Zhi-Shen Huang ◽

Manmohan S. Biring ◽

Bojan Cercek ◽

...

Keyword(s):

Muscle Protein ◽

Muscle Growth ◽

The Body ◽

Diaphragm Muscle ◽

Fiber Types ◽

Mrna Levels ◽

Adult Rats ◽

Cross Sectional ◽

Igf I ◽

The Impact

This study evaluated the impact of varying degrees of prolonged malnutrition on the local insulin-like growth factor-I (IGF-I) system in the costal diaphragm muscle. Adult rats were provided with either 60 or 40% of usual food intake over 3 wk. Nutritionally deprived (ND) animals (i.e., ND60 and ND40) were compared with control (Ctl) rats fed ad libitum. Costal diaphragm fiber types and cross-sectional areas were determined histochemically. Costal diaphragm muscle IGF-I mRNA levels were determined by RT-PCR. Serum and muscle IGF-I peptide levels were determined by using a rat-specific radioimmunoassay. The body weights of Ctl rats increased by 5%, whereas those of ND60 and ND40 animals decreased by 16 and 26%, respectively. Diaphragm weights were reduced by 17 and 27% in ND60 and ND40 animals, respectively, compared with Ctl. Diaphragm fiber proportions were unaffected by either ND regimen. Significant atrophy of both type IIa and IIx fibers was noted in the ND60 group, whereas atrophy of all three fiber types was observed in the diaphragm of ND40 rats. Serum IGF-I levels were reduced by 62 and 79% in ND60 and ND40 rats, respectively, compared with Ctl. Diaphragm muscle IGF-I mRNA levels in both ND groups were similar to those noted in Ctl. In contrast, IGF-I concentrations were reduced by 36 and 42% in the diaphragm muscle of ND60 and ND40 groups, respectively, compared with Ctl. We conclude that the local (autocrine/paracrine) muscle IGF-I system is affected in our models of prolonged ND. We propose that this contributes to disordered muscle protein turnover and muscle cachexia with atrophy of muscle fibers. This is particularly so in view of recent data demonstrating the importance of the autocrine/paracrine system in muscle growth and maintenance of fiber size.

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Resistance training and sarcopenia

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2015.738 ◽

2016 ◽

Vol 84 (1-2) ◽

Cited By ~ 4

Author(s):

Francesco Giallauria ◽

Antonio Cittadini ◽

Neil Andrew Smart ◽

Carlo Vigorito

Keyword(s):

Resistance Training ◽

Muscle Mass ◽

Treatment Options ◽

Muscle Growth ◽

Post Translational Modification ◽

Age Related ◽

Central Nervous Systems ◽

New Treatment ◽

And Function ◽

Hormonal Milieu

Aging is inexorably accompanied by a progressive decline of muscle mass, quality and strength. The resulting condition has been termed sarcopenia. Age-related sarcopenia can be accelerated by a variety of factors including changes in the hormonal milieu, inactivity, poor nutrition, chronic illness, and loss of integrity and function in the peripheral and central nervous systems. The downstream mechanisms by which these risk factors cause sarcopenia are not completely understood. Exercise training (particularly resistance training) has long been identified as the most promising method for increasing muscle mass and strength among older people. New interventions aimed at preventing muscle atrophy, promoting muscle growth and ultimately, maintaining muscle functions during aging are discussed. Understanding how age affects muscle-related gene expression, protein recycling and resynthesis, post-translational modification and turnover will be crucial to identify new treatment options. RiassuntoL’invecchiamento è inesorabilmente accompagnato da un progressivo declino della massa, della qualità e della forza muscolare. La conseguente condizione viene definita sarcopenia. La sarcopenia correlata all’invecchiamento può essere accelerata da una serie di fattori tra cui le modifiche degli equilibri ormonali, la sedentarietà, la scarsa nutrizione, le patologie croniche, e la perdita di integrità e funzione del sistema nervoso centrale e periferico. I meccanismi attraverso i quali questi fattori causano sarcopenia sono ancora non completamente chiari. L’esercizio fisico (in particolare il training di resistenza) è da tempo identificato come una delle più promettenti stratefie per aumentare la massa muscolare e la forza negli anziani. Interventi mirati a prevenire la atrofia muscolare, a promuovere la crescita muscolare e, in ultima analisi, preservare le funzioni muscolari durante l’invecchiamento verranno discussi. Comprendere come l’invecchiamento interferisce con l’espressione genica ai livello muscolare, con i sistemi di riciclo e resintesi proteica, con le modifiche post-traslatzionali e il turnover, sarà cruciale per identificare e implementare nuove strategie terapeutiche.

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The Hamstrings: Anatomic and Physiologic Variations and Their Potential Relationships With Injury Risk

Frontiers in Physiology ◽

10.3389/fphys.2021.694604 ◽

2021 ◽

Vol 12 ◽

Author(s):

José Afonso ◽

Sílvia Rocha-Rodrigues ◽

Filipe M. Clemente ◽

Michele Aquino ◽

Pantelis T. Nikolaidis ◽

...

Keyword(s):

Risk Factors ◽

Injury Risk ◽

Individual Characteristics ◽

Individual Risk ◽

Modifiable Risk Factors ◽

Fiber Types ◽

Cross Sectional ◽

Exercise Interventions ◽

Age Related ◽

The Individual

The incidence and recurrence of hamstrings injuries are very high in sports, posing elevated performance and financial-related costs. Attempts to identify the risk factors involved in predicting vulnerability to hamstrings injury is important for designing exercise-based programs that aim to mitigate the rate and severity of hamstrings injuries and improve rehabilitation strategies. However, research has shown that non-modifiable risk factors may play a greater role than modifiable risk factors. Recognizing non-modifiable risk factors and understanding their implications will afford the prescription of better suited exercise programs, i.e., that are more respectful of the individual characteristics. In a nutshell, non-modifiable risk factors can still be acted upon, even if indirectly. In this context, an underexplored topic is how intra and inter- individual anatomic and physiologic variations in hamstrings (e.g., muscle bellies, fiber types, tendon length, aponeurosis width, attachment sites, sex- and age-related differences) concur to alter hamstrings injuries risk. Some anatomic and physiologic variations may be modifiable through exercise interventions (e.g., cross-sectional area), while others may not (e.g., supernumerary muscle bellies). This apparent dichotomy may hide a greater complexity, i.e., there may be risk factors that are partially modifiable. Therefore, we explored the available information on the anatomic variations of the hamstrings, providing a deeper insight into the individual risk factors for hamstrings injuries and contributing with better knowledge and potential applications toward a more individualized exercise prescription.

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Ablation of S1P3 receptor protects mouse soleus from age-related drop in muscle mass, force, and regenerative capacity

AJP Cell Physiology ◽

10.1152/ajpcell.00027.2017 ◽

2017 ◽

Vol 313 (1) ◽

pp. C54-C67 ◽

Cited By ~ 5

Author(s):

Michela Bondì ◽

Elena Germinario ◽

Marco Pirazzini ◽

Giulia Zanetti ◽

Francesca Cencetti ◽

...

Keyword(s):

Muscle Mass ◽

Soleus Muscle ◽

Contractile Properties ◽

Mass Force ◽

Wild Type ◽

Regenerative Capacity ◽

Cross Sectional ◽

Adult Mice ◽

Age Related ◽

The Mean

We investigated the effects of S1P3 deficiency on the age-related atrophy, decline in force, and regenerative capacity of soleus muscle from 23-mo-old male (old) mice. Compared with muscle from 5-mo-old (adult) mice, soleus mass and muscle fiber cross-sectional area (CSA) in old wild-type mice were reduced by ~26% and 24%, respectively. By contrast, the mass and fiber CSA of soleus muscle in old S1P3-null mice were comparable to those of adult muscle. Moreover, in soleus muscle of wild-type mice, twitch and tetanic tensions diminished from adulthood to old age. A slowing of contractile properties was also observed in soleus from old wild-type mice. In S1P3-null mice, neither force nor the contractile properties of soleus changed during aging. We also evaluated the regenerative capacity of soleus in old S1P3-null mice by stimulating muscle regeneration through myotoxic injury. After 10 days of regeneration, the mean fiber CSA of soleus in old wild-type mice was significantly smaller (−28%) compared with that of regenerated muscle in adult mice. On the contrary, the mean fiber CSA of regenerated soleus in old S1P3-null mice was similar to that of muscle in adult mice. We conclude that in the absence of S1P3, soleus muscle is protected from the decrease in muscle mass and force, and the attenuation of regenerative capacity, all of which are typical characteristics of aging.

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