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Frailty in aging is driven by the dysregulation of multiple biological pathways. Protectin DX (PDX) is a docosahexaenoic acid (DHA)-derived molecule that alleviates many chronic inflammatory disorders, but its potential effects on frailty remain unknown. Our goal is to identify age-related impairments in metabolic systems and to evaluate the therapeutic potential of PDX on frailty, physical performance, and health parameters. A set of 22-month-old C57BL/6 male and female mice were assigned to vehicle (Old) or PDX daily gavage treatment for 9 weeks, whereas 6-month-old (Adult) mice received only vehicle. Forelimb and hindlimb strength, endurance, voluntary wheel activity and walking speed determined physical performance and were combined with a frailty index score and body weight loss to determine frailty status. Our data shows that old vehicle-treated mice from both sexes had body weight loss paralleling visceromegaly, and Old females also had impaired insulin clearance as compared to the Adult group. Aging was associated with physical performance decline together with higher odds of frailty development. There was also age-driven mesangial expansion and glomerular hypertrophy as well as bone mineral density loss. All of the in vivo and in vitro impairments observed with aging co-occurred with upregulation of inflammatory pathways and Myc signaling as well as downregulation of genes related to adipogenesis and oxidative phosphorylation in liver. PDX attenuated the age-driven physical performance (strength, exhaustion, walking speed) decline, promoted robustness, prevented bone losses and partially reversed changes in hepatic expression of Myc targets and metabolic genes. In conclusion, our data provides evidence of the beneficial therapeutic effect of PDX against features of frailty in mice. Further studies are warranted to investigate the mechanisms of action and the potential for human translation.
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Ácidos Docosahexaenoicos , Fragilidad , Ratones , Masculino , Humanos , Femenino , Animales , Ácidos Docosahexaenoicos/farmacología , Ácidos Docosahexaenoicos/uso terapéutico , Transducción de Señal , Fragilidad/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-myc/farmacología , Ratones Endogámicos C57BL , Pérdida de PesoRESUMEN
Frailty is a complex syndrome affecting a growing sector of the global population as medical developments have advanced human mortality rates across the world. Our current understanding of frailty is derived from studies conducted in the laboratory as well as the clinic, which have generated largely phenotypic information. Far fewer studies have uncovered biological underpinnings driving the onset and progression of frailty, but the stage is set to advance the field with preclinical and clinical assessment tools, multiomics approaches together with physiological and biochemical methodologies. In this article, we provide comprehensive coverage of topics regarding frailty assessment, preclinical models, interventions, and challenges as well as clinical frameworks and prevalence. We also identify central biological mechanisms that may be at play including mitochondrial dysfunction, epigenetic alterations, and oxidative stress that in turn, affect metabolism, stress responses, and endocrine and neuromuscular systems. We review the role of metabolic syndrome, insulin resistance and visceral obesity, focusing on glucose homeostasis, adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and nicotinamide adenine dinucleotide (NAD+ ) as critical players influencing the age-related loss of health. We further focus on how immunometabolic dysfunction associates with oxidative stress in promoting sarcopenia, a key contributor to slowness, weakness, and fatigue. We explore the biological mechanisms involved in stem cell exhaustion that affect regeneration and may contribute to the frailty-associated decline in resilience and adaptation to stress. Together, an overview of the interplay of aging biology with genetic, lifestyle, and environmental factors that contribute to frailty, as well as potential therapeutic targets to lower risk and slow the progression of ongoing disease is covered. © 2022 American Physiological Society. Compr Physiol 12:1-46, 2022.
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Fragilidad , Resistencia a la Insulina , Envejecimiento/fisiología , Humanos , Estrés Oxidativo , Estados UnidosRESUMEN
The prevalence of frailty across the world in older adults is increasing dramatically and having frailty places a person at increased risk for many adverse health outcomes, including impaired mobility, falls, hospitalizations, and mortality. Globally, the concept of frailty is gaining attention and the scientific field has made great strides in identifying and conceptually defining frailty through consensus conferences, in advancing the overall science of frailty by drawing on basic science discoveries including concepts surrounding the hallmarks of aging, resilience, and intrinsic capacities, and in identifying the many challenges faced by professionals within diverse clinical settings. Currently, it is thought that frailty is preventable, thus the identification of a person's degree of frailty is vital. Identification of frailty is achievable through widely used frailty screening tools, which are valid, reliable, and easy to use. Following the identification of a person's degree of frailty, targeted intervention strategies, such as physical activity programs must be implemented. In this perspective, we provide a historical perspective of the frailty field since the last quarter of the 20th century to present. We identify the proposed underlying pathophysiology of multiple physiological systems, including compromised homeostasis and resilience. Next, we outline the available screening tools for frailty with a physical performance assessment and highlight specific benefits of physical activity. Lastly, we discuss current scientific evidence supporting the physical activity recommendations for the aging population and for older adults with frailty. The goal is to emphasize early detection of frailty and stress the value of physical activity.
RESUMEN
The underlying mechanisms contributing to the onset of frailty, its progression, and its mortality risk remain unknown. Recently, the two most common human frailty assessments were reverse-translated to mice. Here, we highlight the development of the mouse frailty phenotype, unique discoveries, experimental considerations, and future perspectives.
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Modelos Animales de Enfermedad , Fragilidad/fisiopatología , Factores de Edad , Animales , Humanos , Ratones , FenotipoRESUMEN
Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease. Although the lack of dystrophin protein is the primary defect responsible for the development of DMD, secondary disease complications such as persistent inflammation contribute greatly to the pathogenesis and the time-dependent progression of muscle destruction. The immunoproteasome is a potential therapeutic target for conditions or diseases mechanistically linked to inflammation. In this study, we explored the possible effects of ONX-0914 administration, an inhibitor specific for the immunoproteasome subunit LMP7 (ß5i), on motor performance, muscular pathology and protein degradation in 7-week old MDX mice, an age when the dystrophic muscles show extensive degeneration and regeneration. ONX-0914 (10 mg/kg) was injected subcutaneously on Day 2, 4, and 6. The mice were evaluated for physical performance (walking speed and strength) on Day 1 and 8. We show that this short-term treatment of ONX-0914 in MDX mice did not alter strength nor walking speed. The physical performance findings were consistent with no change in muscle inflammatory infiltration, percentage of central nuclei and proteasome content. Taken together, muscle structure and function in the young adult MDX mouse model are not altered with ONX-0914 treatment, indicating the administration of ONX-0914 during this critical time period does not exhibit any detrimental effects and may be an effective treatment of secondary complications of muscular dystrophy after further investigations.
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Distrofina , Músculo Esquelético , Distrofia Muscular de Duchenne/tratamiento farmacológico , Oligopéptidos , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Músculo Esquelético/efectos de los fármacos , Oligopéptidos/farmacología , Fenotipo , Adulto JovenRESUMEN
Preclinical studies are important in identifying the underlying mechanisms contributing to frailty. Frailty studies have mainly focused on male rodents with little directed at female rodents. Therefore, the purposes of this study were to identify the onset and prevalence of frailty across the life span in female mice, and to determine if frailty predicts mortality. Female C57BL/6 (n = 27) mice starting at 17 months of age were assessed across the life span using a frailty phenotype, which included body weight, walking speed, strength, endurance, and physical activity. The onset of frailty occurred at approximately 17 months (1/27 mice), with the prevalence of frailty increasing thereafter. At 17 months, 11.1% of the mice were pre-frail and by 26 months peaked at 36.9%. The percentage of frail mice progressively increased up to 66.7% at 32 months. Non-frail mice lived to 29 months whereas frail/pre-frail mice lived only to 26 months (p = .04). In closing, using a mouse frailty phenotype, we are able to identify that the prevalence of frailty in female mice increases across the life span and accurately predicts mortality. Together, this frailty phenotype has the potential to yield information about the underlying mechanisms contributing to frailty.
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Envejecimiento/patología , Envejecimiento/fisiología , Fragilidad/patología , Fragilidad/fisiopatología , Anciano , Animales , Peso Corporal , Modelos Animales de Enfermedad , Femenino , Anciano Frágil , Fuerza de la Mano , Humanos , Longevidad/fisiología , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Fenotipo , Resistencia Física , CaminataRESUMEN
In skeletal muscles, calorie restriction (CR) preserves muscle mass in middle-aged rats but not younger rats. The underlying mechanisms for this age-specific response are unknown. Skeletal muscle mass depends on several factors, with protein synthesis and degradation playing major roles. Therefore, the purpose of this study was to investigate whether CR affects younger and older animals differently on mTOR signaling and ubiquitin-proteasome pathway (UPP). Four-, 8-, and 16-month-old rats, with or without 40% CR for a duration of 14 weeks, were sacrificed after an overnight fasting. Total protein content and the phosphorylation level of AKT, mTOR, S6K, and 4EBP1 and protein content of key markers in the UPP (FOXO3a, atrogin, MuRF1, ubiquitinated proteins, proteasome subunits alpha 7 and beta 5) were determined. Unlike younger rats, CR decreased the content of phosphorylated mTOR, S6K, phosphorylated S6K, FOXO3a, and ubiquitinated proteins in middle-aged rats. In conclusion, CR-induced reduction of content/ phosphorylation levels of key proteins in mTOR signaling and the UPP occurred in the middle-aged rats but not younger rats. The age-dependent effects of CR on mTOR signaling and the UPP indirectly explained the age-related effects of CR on muscle mass of animals.
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Envejecimiento/fisiología , Restricción Calórica/métodos , Músculo Esquelético/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Ubiquitina/metabolismo , Animales , Western Blotting , Modelos Animales de Enfermedad , Masculino , Músculo Esquelético/patología , Fosforilación , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
Many age-related biochemical, physiological and behavioral changes are known to be sex-specific. However, how sex influences frailty status and mortality risk in frail rodents has yet to be established. The purpose of this study was therefore to characterize sex differences in frail mice across the lifespan. Male (n=29) and female (n=27) mice starting at 17 months of age were assessed using a frailty phenotype adjusted according to sex, which included body weight, walking speed, strength, endurance and physical activity. Regardless of sex, frail mice were phenotypically dysfunctional compared to age-matched non-frail mice, while non-frail females generally possessed a higher body fat percentage and were more physically active than non-frail males (p≤0.05). The prevalence of frailty was greater in female mice at 26 months of age (p=0.05), but if normalized to mean lifespan, no sex differences remained. No differences were detected in the rate of death or mean lifespan between frail male and female mice (p≥0.12). In closing, these data indicate that sexual differences exist in aging C57BL/6 mice and if the frailty criteria are adjusted according to sex, the prevalence of frailty increases across age with frail mice dying early in life, regardless of sex.
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Envejecimiento/fisiología , Fragilidad , Caracteres Sexuales , Animales , Femenino , Longevidad , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Sarcopenia, the age-related loss of muscle mass and strength, contributes to frailty, functional decline, and reduced quality of life in older adults. Exercise is a recognized therapy for sarcopenia and muscle dysfunction, though not a cure. Muscle power declines at an increased rate compared to force, and force output declines earlier than mass. Thus, there is a need for research of exercise focusing on improving power output and functionality in older adults. Our primary purpose was proof-of-concept that a novel individualized power exercise modality would induce positive adaptations in adult mice, before the exercise program was applied to an aged cohort. We hypothesized that after following our protocol, both adult and older mice would show improved function, though there would be evidence of anabolic resistance in the older mice. Male C57BL/6 mice (12 months of age at study conclusion) were randomized into control (n = 9) and exercise (n = 6) groups. The trained group used progressive resistance (with a weighted harness) and intensity (~ 4-10 rpm) on a custom motorized running wheel. The mice trained similarly to a human workout regimen (4-5 sets/session, 3 sessions/week, for 12 weeks). We determined significant (p < 0.05) positive adaptations post-intervention, including: neuromuscular function (rotarod), strength/endurance (inverted cling grip test), training physiology (force/power output per session), muscle size (soleus mass), and power/velocity of contraction (in vitro physiology). Secondly, we trained a cohort of older male mice (28 months old at conclusion): control (n = 12) and exercised (n = 8). While the older exercised mice did preserve function and gain benefits, they also demonstrated evidence of anabolic resistance.
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Adaptación Fisiológica , Fuerza Muscular/fisiología , Condicionamiento Físico Animal/métodos , Entrenamiento de Fuerza/métodos , Sarcopenia/rehabilitación , Adulto , Factores de Edad , Anciano , Envejecimiento/fisiología , Animales , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Distribución Aleatoria , Valores de Referencia , Factores de RiesgoRESUMEN
Disuse induces adaptations in skeletal muscle, which lead to muscle deterioration. Hindlimb-unloading (HU) is a well-established model to investigate cellular mechanisms responsible for disuse-induced skeletal muscle dysfunction. In myosin heavy chain (MHC) type IIB fibers HU induces a reduction in contraction speed (Vo) and a reduction in the relative myosin light chain 3f (MLC3f) protein content compared with myosin light chain 1f (MLC1f) protein. This study tested the hypothesis that increasing the relative MLC3f protein content via rAd-MLC3f vector delivery would attenuate the HU-induced decline in Vo in single MHC type IIB fibers. Fischer-344 rats were randomly assigned to one of three groups: control, HU for 7 days, and HU for 7 days plus rAd-MLC3f. The semimembranosus muscles were injected with rAd-MLC3f (3.75 x 1011-5 x 1011 ifu/ml) at four days after the initiation of HU. In single MHC type IIB fibers the relative MLC3f content decreased by 25% (12.00±0.60% to 9.06±0.66%) and Vo was reduced by 29% (3.22±0.14fl/s vs. 2.27±0.08fl/s) with HU compared to the control group. The rAd-MLC3f injection resulted in an increase in the relative MLC3f content (12.26±1.19%) and a concomitant increase in Vo (2.90±0.15fl/s) of MHC type IIB fibers. A positive relationship was observed between the percent of MLC3f content and Vo. Maximal isometric force and specific tension were reduced with HU by 49% (741.45±44.24µN to 379.09±23.77µN) and 33% (97.58±4.25kN/m2 to 65.05±2.71kN/m2), respectively compared to the control group. The rAd-MLC3f injection did not change the HU-induced decline in force or specific tension. Collectively, these results indicate that rAd-MLC3f injection rescues hindlimb unloading-induced decline in Vo in MHC type IIB single muscle fibers.
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Adaptación Fisiológica , Contracción Muscular , Fibras Musculares Esqueléticas/metabolismo , Trastornos Musculares Atróficos/prevención & control , Cadenas Ligeras de Miosina/biosíntesis , Adenoviridae , Animales , Vectores Genéticos , Suspensión Trasera , Masculino , Fibras Musculares Esqueléticas/patología , Trastornos Musculares Atróficos/genética , Trastornos Musculares Atróficos/metabolismo , Cadenas Ligeras de Miosina/genética , Ratas , Ratas Endogámicas F344 , Transducción GenéticaRESUMEN
Unilateral denervation is widely used for studies investigating mechanisms of muscle atrophy. The "contralateral-innervated muscle" is a commonly used experimental control in denervation studies. It is not clear whether denervation unilaterally alters the proteolytic system in the contralateral-innervated muscles. Therefore, the objectives of this rapid report are 1) to determine whether unilateral denervation has an effect on the proteolytic system in contralateral-innervated control muscles and 2) to identify the changes in proteasome properties in denervated muscles after 7- and 14-day tibial nerve transection with either the contralateral-innervated muscles or intact muscles from nonsurgical mice used as the experimental control. In the contralateral-innervated muscles after 7 and 14 days of nerve transection, the proteasome activities and content are significantly increased compared with muscles from nonsurgical mice. When the nonsurgical mice are used as the experimental control, a robust increase in proteasome properties is found in the denervated muscles. This robust increase in proteasome properties is eliminated when the contralateral-innervated muscles are the experimental control. In conclusion, there is a crossover effect from unilateral denervation on proteolytic parameters. As a result, the crossover effect on contralateral-innervated muscles must be considered when an experimental control is selected in a denervation study.
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Músculo Esquelético/inervación , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Desnervación Muscular/métodos , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
OBJECTIVE: The aim of this study was to evaluate adaptations in soleus and tibialis anterior muscles in a rat model 4 wks after hemorrhagic stroke. DESIGN: Young adult Sprague Dawley rats were randomly assigned to two groups: stroke and control, with eight soleus and eight tibialis anterior muscles per group. Hemorrhagic stroke was induced in the right caudoputamen of the stroke rats. Control rats had no intervention. Neurologic status was evaluated in both groups before stroke and 4 wks after stroke. Muscles were harvested after poststroke neurologic testing. Muscle fiber types and cross-sectional areas were determined in soleus and tibialis anterior using immunohistochemical labeling for myosin heavy chain. RESULTS: No generalized fiber atrophy was found in any of the muscles. Fiber types shifted from faster to slower in the tibialis anterior of the stroke group, but no fiber type shifts occurred in the soleus muscles of stroke animals. CONCLUSIONS: Because slower myosin heavy chain fiber types are associated with weaker contractile force and slower contractile speed, this faster to slower fiber type shift in tibialis anterior muscles may contribute to weaker and slower muscle contraction in this muscle after stroke. This finding may indicate potential therapeutic benefit from treatments known to influence fiber type plasticity.
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Adaptación Fisiológica , Miembro Posterior/fisiopatología , Hemorragias Intracraneales/fisiopatología , Fibras Musculares Esqueléticas/fisiología , Accidente Cerebrovascular/fisiopatología , Animales , Modelos Animales de Enfermedad , Hemorragias Intracraneales/etiología , Masculino , Contracción Muscular , Músculo Esquelético , Cadenas Pesadas de Miosina , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/etiologíaRESUMEN
Little is known whether frailty assessments in mice are capable of distinguishing important characteristics of the frailty syndrome. The goals of this study were to identify the onset and the prevalence of frailty across the lifespan and to determine if a frailty phenotype predicts mortality. Body weight, walking speed, strength, endurance and physical activity were assessed in male C57BL/6 mice every three months starting at 14 months of age. Mice that fell in the bottom 20% for walking speed, strength, endurance and physical activity, and in the top 20% for body weight were considered to have a positive frailty marker. The onset of frailty occurred at 17 months, and represented only 3.5% of the mouse cohort. The percentage of frail mice increased with age until basically every mouse was identified as frail. Frail, pre-frail, and non-frail mice had mean survival ages of 27, 29 and 34 months, respectively. In closing, frail mice lack resilience; in that, multiple tissue/organ systems may deteriorate at an accelerated rate and ultimately lead to early mortality when compared to non-frail mice. Identifying the onset and prevalence of frailty, in addition to predicting mortality, has potential to yield information about several aging processes.
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Fragilidad/patología , Fuerza Muscular , Resistencia Física , Caminata/fisiología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad MotoraRESUMEN
Content of the immunoproteasome, the inducible form of the standard proteasome, increases in atrophic muscle suggesting it may be associated with skeletal muscle remodeling. However, it remains unknown if the immunoproteasome responds to stressful situations that do not promote large perturbations in skeletal muscle proteolysis. The purpose of this study was to determine how an acute bout of muscular stress influences immunoproteasome content. To accomplish this, wild-type (WT) and immunoproteasome knockout lmp7 -/- /mecl1 -/- (L7M1) mice were run downhill on a motorized treadmill. Soleus muscles were excised 1 and 3 days post-exercise and compared to unexercised muscle (control). Ex vivo physiology, histology and biochemical analyses were used to assess the effects of immunoproteasome knockout and unaccustomed exercise. Besides L7M1 muscle being LMP7/MECL1 deficient, no other major biochemical, histological or functional differences were observed between the control muscles. In both strains, the downhill run shifted the force-frequency curve to the right and reduced twitch force; however, it did not alter tetanic force or inflammatory markers. In the days post-exercise, several of the proteasome's catalytic subunits were upregulated. Specifically, WT muscle increased LMP7 while L7M1 muscle instead increased ß5. These findings indicate that running mice downhill results in subtle contractile characteristics that correspond to skeletal muscle injury, yet it does not appear to induce a significant inflammatory response. Interestingly, this minor stress activated the production of specific immunoproteasome subunits that if knocked out were replaced by components of the standard proteasome. These data suggest that the immunoproteasome may be involved in maintaining cellular homeostasis.
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Prueba de Esfuerzo , Músculo Esquelético/metabolismo , Condicionamiento Físico Animal , Complejo de la Endopetidasa Proteasomal/inmunología , Animales , Composición Corporal , Inflamación/patología , Masculino , Ratones Endogámicos C57BL , Contracción Muscular/fisiología , Tamaño de los Órganos , Carbonilación ProteicaRESUMEN
The standard 26S proteasome is responsible for the majority of myofibrillar protein degradation leading to muscle atrophy. The immunoproteasome is an inducible form of the proteasome. While its function has been linked to conditions of atrophy, its contribution to muscle proteolysis remains unclear. Therefore, the purpose of this study was to determine if the immunoproteasome plays a role in skeletal muscle atrophy induced by denervation. Adult male C57BL/6 wild type (WT) and immunoproteasome knockout lmp7-/-/mecl-1-/- (L7M1) mice underwent tibial nerve transection on the left hindlimb for either 7 or 14 days, while control mice did not undergo surgery. Proteasome activity (caspase-, chymotrypsin-, and trypsin- like), protein content of standard proteasome (ß1, ß5 and ß2) and immunoproteasome (LMP2, LMP7 and MECL-1) catalytic subunits were determined in the gastrocnemius muscle. Denervation induced significant atrophy and was accompanied by increased activities and protein content of the catalytic subunits in both WT and L7M1 mice. Although denervation resulted in a similar degree of muscle atrophy between strains, the mice lacking two immunoproteasome subunits showed a differential response in the extent and duration of proteasome features, including activities and content of the ß1, ß5 and LMP2 catalytic subunits. The results indicate that immunoproteasome deficiency alters the proteasome's composition and activities. However, the immunoproteasome does not appear to be essential for muscle atrophy induced by denervation.
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Desnervación Muscular , Músculo Esquelético/inmunología , Atrofia Muscular/inmunología , Complejo de la Endopetidasa Proteasomal/inmunología , Animales , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/inmunología , Activación Enzimática/genética , Activación Enzimática/inmunología , Carioferinas/genética , Carioferinas/inmunología , Masculino , Ratones , Ratones Noqueados , Músculo Esquelético/patología , Atrofia Muscular/genética , Atrofia Muscular/patología , Complejo de la Endopetidasa Proteasomal/genéticaRESUMEN
It is well known that the ubiquitin-proteasome system is activated in response to skeletal muscle wasting and functions to degrade contractile proteins. The loss of these proteins inevitably reduces skeletal muscle size (i.e., quantity). However, it is currently unknown whether activation of this pathway also affects function by impairing the muscle's intrinsic ability to produce force (i.e., quality). Therefore, the purpose of this study was twofold, (1) document how the ubiquitin-proteasome system responds to denervation and (2) identify the physiological consequences of these changes. To induce soleus muscle atrophy, C57BL6 mice underwent tibial nerve transection of the left hindlimb for 7 or 14 days (n = 6-8 per group). At these time points, content of several proteins within the ubiquitin-proteasome system were determined via Western blot, while ex vivo whole muscle contractility was specifically analyzed at day 14. Denervation temporarily increased several key proteins within the ubiquitin-proteasome system, including the E3 ligase MuRF1 and the proteasome subunits 19S, α7 and ß5. These changes were accompanied by reductions in absolute peak force and power, which were offset when expressed relative to physiological cross-sectional area. Contrary to peak force, absolute and relative forces at submaximal stimulation frequencies were significantly greater following 14 days of denervation. Taken together, these data represent two keys findings. First, activation of the ubiquitin-proteasome system is associated with reductions in skeletal muscle quantity rather than quality. Second, shortly after denervation, it appears the muscle remodels to compensate for the loss of neural activity via changes in Ca2+ handling.
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Contracción Muscular/fisiología , Desnervación Muscular , Músculo Esquelético/inervación , Atrofia Muscular/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismoRESUMEN
With advancing age, skeletal muscle function declines as a result of strength loss. These strength deficits are largely due to reductions in muscle size (i.e., quantity) and its intrinsic force-producing capacity (i.e., quality). Age-induced reductions in skeletal muscle quantity and quality can be the consequence of several factors, including accumulation of reactive oxygen and nitrogen species (ROS/RNS), also known as oxidative stress. Therefore, the purpose of this mini-review is to highlight the published literature that has demonstrated links between aging, oxidative stress, and skeletal muscle quantity or quality. In particular, we focused on how oxidative stress has the potential to reduce muscle quantity by shifting protein balance in a deficit, and muscle quality by impairing activation at the neuromuscular junction, excitation-contraction (EC) coupling at the ryanodine receptor (RyR), and cross-bridge cycling within the myofibrillar apparatus. Of these, muscle weakness due to EC coupling failure mediated by RyR dysfunction via oxidation and/or nitrosylation appears to be the strongest candidate based on the publications reviewed. However, it is clear that age-associated oxidative stress has the ability to alter strength through several mechanisms and at various locations of the muscle fiber.
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Envejecimiento/fisiología , Músculo Esquelético/fisiología , Estrés Oxidativo/fisiología , Animales , Humanos , Fibras Musculares Esqueléticas/fisiología , Fuerza Muscular/fisiología , Debilidad Muscular/fisiopatologíaRESUMEN
Quantification of key outcome measures in animal models of aging is an important step preceding intervention testing. One such measurement, skeletal muscle power generation (force * velocity), is critical for dynamic movement. Prior research focused on maximum power (P max), which occurs around 30-40 % of maximum load. However, movement occurs over the entire load range. Thus, the primary purpose of this study was to determine the effect of age on power generation during concentric contractions in the extensor digitorum longus (EDL) and soleus muscles over the load range from 10 to 90 % of peak isometric tetanic force (P 0). Adult, old, and elderly male C57BL/6 mice were examined for contractile function (6-7 months old, 100 % survival; ~24 months, 75 %; and ~28 months, <50 %, respectively). Mice at other ages (5-32 months) were also tested for regression modeling. We hypothesized and found that power decreased with age not only at P max but also over the load range. Importantly, we found greater age-associated deficits in both power and velocity when the muscles were contracting concentrically against heavy loads (>50 % P 0). The shape of the force-velocity curve also changed with age (a/P 0 increased). In addition, there were prolonged contraction times to maximum force and shifts in the distribution of the myosin light and heavy chain isoforms in the EDL. The results demonstrate that age-associated difficulty in movement during challenging tasks is likely due, in addition to overall reduced force output, to an accelerated deterioration of power production and contractile velocity under heavily loaded conditions.
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Envejecimiento/fisiología , Contracción Isométrica/fisiología , Ratones Endogámicos C57BL/fisiología , Músculo Esquelético/fisiología , Sarcopenia/fisiopatología , Animales , Masculino , Ratones , Fuerza Muscular/fisiologíaRESUMEN
Frailty is a major cause of disability and loss of independence in the elderly. Using clinically relevant criteria from our previously established mouse frailty index, we investigated the effects of aerobic exercise on frailty in male C57BL/6 mice. In order to measure the effect of treatment on the individual animals, we constructed a composite score, the Frailty Intervention Assessment Value. We hypothesized voluntary aerobic exercise would improve individual criteria and reverse or prevent frailty in the old mice. Five adult and 11 old mice (6 and 28+ months, respectively) were housed individually in cages with running wheels for 4 weeks. Controls (adult, n = 5 and old, n = 17) were housed without wheels. Inverted cling grip and rotarod tests were performed pre- and postintervention. Hind limb muscles were used for biochemical analysis and contractility experiments. We conclude that the exercise stimulus reversed frailty and was sufficient to maintain or improve functional performance in old mice, as well as to produce measurable morphological changes. In addition, the Frailty Intervention Assessment Value proved to be a valuable tool with increased power to detect treatment effects and to examine the intervention efficacy at the level of the individual mouse.
Asunto(s)
Envejecimiento , Condicionamiento Físico Animal , Animales , Miembro Anterior , Miembro Posterior , Masculino , Ratones Endogámicos C57BL , Contracción Muscular , Fibras Musculares de Contracción Rápida/patología , Fuerza Muscular , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Cadenas Pesadas de Miosina/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Resistencia Física , Isoformas de Proteínas/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Increased proteasome activity has been implicated in the atrophy and deterioration associated with dystrophic muscles of Duchenne muscular dystrophy (DMD). While proteasome inhibitors show promise in the attenuation of muscle degeneration, proteasome inhibition-induced toxicity was a major drawback of this therapeutic strategy. Inhibitors that selectively target the proteasome subtype that is responsible for the loss in muscle mass and quality would reduce side effects and be less toxic. This study examined proteasome activity and subtype populations, along with muscle function, morphology and damage in wild-type (WT) mice and two murine models of DMD, dystrophin-deficient (MDX) and dystrophin- and utrophin-double-knockout (DKO) mice. We found that immunoproteasome content was increased in dystrophic muscles while the total proteasome content was unchanged among the three genotypes of mice. Proteasome proteolytic activity was elevated in dystrophic muscles, especially in DKO mice. These mice also exhibited more severe muscle atrophy than either WT or MDX mice. Muscle damage and regeneration, characterized by the activity of muscle creatine kinase in the blood and the percentage of central nuclei were equally increased in dystrophic mice. Accordingly, the overall muscle function was similarly reduced in both dystrophic mice compared with WT. These data demonstrated that there was transformation of standard proteasomes to immunoproteasomes in dystrophic muscles. In addition, DKO that showed greatest increase in proteasome activities also demonstrated more severe atrophy compared with MDX and WT. These results suggest a putative role for the immunoproteasome in muscle deterioration associated with DMD and provide a potential target for therapeutic intervention.