Age-related Loss Of Muscle Function Research Articles

Effects of a ketogenic diet on motor function and motor unit number estimation in aged C57BL/6 mice

ObjectivePathological, age-related loss of muscle function, commonly referred to as sarcopenia, contributes to loss of mobility, impaired independence, as well as increased risk of adverse health events. Sarcopenia has been attributed to changes in both neural and muscular integrity during aging. Current treatment options are primarily limited to exercise and dietary protein fortification, but the therapeutic impact of these approaches are often inadequate. Prior work has suggested that a ketogenic diet (KD) might improve healthspan and lifespan in aging mice. Thus, we sought to investigate the effects of a KD on neuromuscular indices of sarcopenia in aged C57BL/6 mice. DesignA randomized, controlled pre-clinical experiment consisting of longitudinal assessments performed starting at 22-months of age (baseline) as well as 2, 6 and 10 weeks after the start of a KD vs. regular chow intervention. SettingPreclinical laboratory study. Sample sizeThirty-six 22-month-old mice were randomized into 2 dietary groups: KD [n = 22 (13 female and 9 male)], and regular chow [n = 15 (7 female and 8 male)]. MeasurementsMeasures included body mass, hindlimb and all limb grip strength, rotarod for motor performance, plantarflexion muscle contractility, motor unit number estimations (MUNE), and repetitive nerve stimulation (RNS) as an index of neuromuscular junction transmission efficacy recorded from the gastrocnemius muscle. At end point, muscle wet weight and blood samples were collected to assess blood beta-hydroxybutyrate levels. Statistical analysisPrimary analyses were two-way mixed effects ANOVA (diet and time × diet) to determine the effect of a KD on indices of motor function (grip, rotarod) and indices of motor unit (MUNE) and muscle (contractility) function. ResultsBeta-hydroxybutyrate (BHB) was significantly higher at 10 weeks in mice on a KD vs control group (0.83 ± 0.44 mmol/l versus 0.42 ± 0.21 mmol/l, η2 = 0.265, unpaired t-test, p = 0.0060). Mice on the KD intervention demonstrated significantly increased hindlimb grip strength (diet, p = 0.0001; time × diet, p = 0.0030), all limb grip strength (diet, p = 0.0005; time × diet, p = 0.0523), and rotarod latency to fall (diet, p = 0.0126; time × diet, p = 0.0021). Mice treated with the KD intervention also demonstrated increased MUNE (diet, p = 0.0465; time × diet, p = 0.0064), but no difference in muscle contractility (diet, p = 0.5248; time × diet, p = 0.5836) or RNS (diet, p = 0.3562; time × diet, p = 0.9871). ConclusionKD intervention improved neuromuscular and motor function in aged mice. This pre-clinical work suggests that further research is needed to assess the efficacy and physiological effects of a KD on indices of sarcopenia.

1894 Enhancing detection of possible sarcopenia and delivery of targeted physiotherapy interventions among hospitalised older patient

Abstract Introduction Sarcopenia, defined as age-related loss of muscle function and strength, has a reported prevalence of up to 40.4% in the older adult. Despite its association with frailty, disability and mortality, it is underdiagnosed among hospitalised older patients. Exercise interventions have also been shown to improve fall risk scores for sarcopenic patients. A QI initiative was started by a team comprising doctors and physiotherapists. Method Our aim was to enhance detection of possible sarcopenia and reduce time to delivery of targeted physiotherapy interventions to 1 working day from admission in patients aged > 65 admitted to our ward. Interventions were grouped into three main categories – strength training, balance and gait stability training. A pilot study of 12 patients showed that no sarcopenia assessments were carried out and mean time to PT review was 2.6 days from admission, with an average of 1.08 interventions performed per patient. Fishbone analysis and Pareto chart were conducted to identify and prioritise factors behind low screening rates of sarcopenia, before driver diagram was performed to develop solutions. Our team established that education of junior doctors on sarcopenia and implementation of SARC-CAIF screening were the most appropriate interventions to achieve our objective. Results A total of 26 patients were identified, with an average age of 76.7 [6.7] years old. The mean SARC-F and SARC-CaIF scores were 4.51 [3.5] and 14.6 [2.4] respectively. 50% (13/26) of patients were admitted for falls. After implementation of SARC-CaIF screening, mean time to PT review was shortened to 1.38 days from admission, with an increase in PT interventions to 2.23 per patient. Prevalence of possible sarcopenia is high among inpatients. Conclusion More can be done to enhance its detection among frail hospitalized older patients, so as to deliver targeted physiotherapy interventions. Doctor education and SARC-CaIF screen are simple and practical tools that can be utilised.

Targeting ryanodine receptors to treat human diseases.

This Review provides an update on ryanodine receptors (RyRs) and their role in human diseases of heart, muscle, and brain. Calcium (Ca2+) is a requisite second messenger in all living organisms. From C. elegans to mammals, Ca2+ is necessary for locomotion, bodily functions, and neural activity. However, too much of a good thing can be bad. Intracellular Ca2+ overload can result in loss of function and death. Intracellular Ca2+ release channels evolved to safely provide large, rapid Ca2+ signals without exposure to toxic extracellular Ca2+. RyRs are intracellular Ca2+ release channels present throughout the zoosphere. Over the past 35 years, our knowledge of RyRs has advanced to the level of atomic-resolution structures revealing their role in the mechanisms underlying the pathogenesis of human disorders of heart, muscle, and brain. Stress-induced RyR-mediated intracellular Ca2+ leak in the heart can promote heart failure and cardiac arrhythmias. In skeletal muscle, RyR1 leak contributes to muscle weakness in inherited myopathies, to age-related loss of muscle function and cancer-associated muscle weakness, and to impaired muscle function in muscular dystrophies, including Duchenne. In the brain, leaky RyR channels contribute to cognitive dysfunction in Alzheimer's disease, posttraumatic stress disorder, and Huntington's disease. Novel therapeutics targeting dysfunctional RyRs are showing promise.

Exploration of mitochondrial defects in sarcopenic hip fracture patients

Severe cases of age-related loss of muscle function and mass are clinically unique to sarcopenia. Mitochondrial dysfunction has been associated with aging and sarcopenia, but the causal connection in this context is not well eluded. Here we investigated different aspects of mitochondrial respiration in sarcopenia. Open muscle biopsies were taken from a total of 31 hip fracture patients, older than 70 years. Patients were assigned a sarcopenia Z-score based on EWGSOP2 criteria. Primary myoblast cultures were generated from the muscle tissue samples and used for real time metabolic measurement. Muscle and serum samples showed correlation of high Z-scores with reduced mitochondrial complex I activity, increased tricarboxylic acid cycle (TCA) metabolites, reduced vitamin D3 levels, and signs of an altered iron metabolism. Primary myoblast cultures gained from the same muscle biopsies did not show significant mitochondrial defects. We hypothesize that a sum of external consequences, including vitamin D3 deficiency and iron deficiency caused by disturbances in the iron metabolism, result in complex I deficiency, which in turn affects the TCA and contributes to muscle weakness and loss.

Preserved Capacity for Adaptations in Strength and Muscle Regulatory Factors in Elderly in Response to Resistance Exercise Training and Deconditioning.

Aging is related to an inevitable loss of muscle mass and strength. The mechanisms behind age-related loss of muscle tissue are not fully understood but may, among other things, be induced by age-related differences in myogenic regulatory factors. Resistance exercise training and deconditioning offers a model to investigate differences in myogenic regulatory factors that may be important for age-related loss of muscle mass and strength. Nine elderly (82 ± 7 years old) and nine young, healthy persons (22 ± 2 years old) participated in the study. Exercise consisted of six weeks of resistance training of the quadriceps muscle followed by eight weeks of deconditioning. Muscle biopsy samples before and after training and during the deconditioning period were analyzed for MyoD, myogenin, insulin-like growth-factor I receptor, activin receptor IIB, smad2, porin, and citrate synthase. Muscle strength improved with resistance training by 78% (95.0 ± 22.0 kg) in the elderly to a similar extent as in the young participants (83.5%; 178.2 ± 44.2 kg) and returned to baseline in both groups after eight weeks of deconditioning. No difference was seen in expression of muscle regulatory factors between elderly and young in response to exercise training and deconditioning. In conclusion, the capacity to gain muscle strength with resistance exercise training in elderly was not impaired, highlighting this as a potent tool to combat age-related loss of muscle function, possibly due to preserved regulation of myogenic factors in elderly compared with young muscle.

Parkin the progression of sarcopenia.

Parkin the progression of sarcopenia.

Age-related remodelling of the myotendinous junction in the mouse soleus muscle

The age-related loss of muscle mass and function predominantly affect muscles of the lower limbs and have largely been associated with decline in muscle fibre size and number, although the exact mechanisms underlying these losses are poorly understood. In addition, consistent reports that the loss of muscle strength exceeds that which can be explained by declines in muscle mass has widened the search for causes of sarcopenia to include supporting tissues such as the extracellular matrix and tendons. Although the changes to both muscle and tendon with age are well characterised, little work has focused on the interface between these two tissues, the myotendinous junction (MTJ). Given the crucial role for this structure in force transfer between muscle and tendon, we asked whether the myotendinous junction underwent structural changes with age in lower limb muscle. We used whole muscle to assess gross muscle and tendon morphology, and immunohistochemistry to determine fibre and MTJ profile number in young (6 months), middle aged (18 months) and elderly (24 months) C57BL/6 female mice. MTJ length was quantified using serial cross sections of the soleus muscle. We found an apparent 3.5-fold increase in MTJ profiles per cross section with no increase in fibre number in old mice, and found this to be a result of a doubling in length of the MTJ region with age. This coincided with an increase in proximal tendon length (31%), as well as an increase in collagen deposition between 6 and 24-months of age consistent with an expansion of the fibre termination area. These findings uncover a previously undescribed effect of ageing on the MTJ and open up new lines of investigation into the role of this structure in the age-related loss of muscle function.

Isolation of Skeletal Muscle Stem Cells for Phenotypic Screens for Modulators of Proliferation.

Adult skeletal muscle contains a population of resident stem cells known as muscle stem cells (MuSC) or satellite cells. This population of cells is required for regeneration of functional myofibers after damage. Aging reduces the proliferative response of satellite cells post-injury. This deficient response is thought to contribute to slowed recovery of muscle function after damage in the elderly and may also contribute to age-related loss of muscle function (sarcopenia). Numerous techniques are now available for the isolation of highly purified satellite cells from mice and humans (Sherwood, et al. Cell 119:543-554, 2004; Cerletti, et al. Cell 134:37-47; 2008; Conboy, et al. Methods Mol Biol 621:165-173, 2010; Bareja, et al. PLoS One 9:e90398; 2014; Castiglioni et al. Stem Cell Rep 2:92-106, 2014; Charville, et al. Stem Cell Rep 5:621-632, 2015; Liu et al. Nat Protoc 10:1612-1624, 2015; Sincennes et al. Methods Mol Biol 1556:41-50, 2017), thus opening an opportunity to use satellite cells in phenotypic screens for regulators of satellite cell proliferation and differentiation. In this chapter, we describe a technique for the prospective isolation of mouse satellite cells that we have recently used in a phenotypic screen of a focused set of small molecules.

Nutritional Interventions in Age-related Loss of Muscle Function

Nutritional Interventions in Age-related Loss of Muscle Function

OR09: Supplementation with Curcumin Improved Age-Related Loss of Muscle Function in Old Rats

OR09: Supplementation with Curcumin Improved Age-Related Loss of Muscle Function in Old Rats

Workshop report: Can an understanding of the mechanisms underlying age-related loss of muscle mass and function guide exercise and other intervention strategies?

An international workshop was hosted by the University of Liverpool on 15–16 July 2011 to address at a basic level what is known about the fundamental mechanisms by which skeletal muscle mass and function are lost during aging and to examine the nature of interventions that might prevent these mechanistic changes. Of particular importance was to attempt to evaluate how different forms of exercise (or muscle contractile activity) influence these processes and how these effects can be best optimized to prevent or delay age-related loss of muscle function. The program took the form of a two-day meeting, comprising a series of invited talks and breakout sessions designed to identify key gaps in current knowledge and potential future research questions. The aims of this Workshop were two-fold: 1. To identify the current state-of-the-art in the understanding of the mechanisms that contribute to loss of skeletal muscle mass and function that occurs with aging and to address at a mechanistic level how, and to what extent, exercise and/or other interventions might prevent these changes. 2. To identify specific areas of research where information is sparse but which are likely to yield data that will impact on future strategies to manipulate age-related loss of muscle mass and function in older people. The areas discussed in detail were loss of functional motor units, reduced muscle stem cell activity, age-related changes in transcriptional responses of muscle to exercise and nutrition, age-related changes in protein homeostasis, mitochondrial function, altered cross-talk between muscle with immune cells and how the developments in basic science to understand mechanisms underlying age-related loss of muscle mass and function can be translated. Following each session three key areas where further studies are needed were identified.

Ryanodine Receptor Oxidation Causes Intracellular Calcium Leak and Muscle Weakness in Aging

Age-related loss of muscle mass and force (sarcopenia) contributes to disability and increased mortality. Ryanodine receptor 1 (RyR1) is the skeletal muscle sarcoplasmic reticulum calcium release channel required for muscle contraction. RyR1 from aged (24months) rodents was oxidized, cysteine-nitrosylated, and depleted of the channel-stabilizing subunit calstabin1, compared to RyR1 from younger (3-6months) adults. This RyR1 channel complex remodeling resulted in "leaky" channels with increased open probability, leading to intracellular calcium leak in skeletal muscle. Similarly, 6-month-old mice harboring leaky RyR1-S2844D mutant channels exhibited skeletal muscle defects comparable to 24-month-old wild-type mice. Treating aged mice with S107 stabilized binding of calstabin1 to RyR1, reduced intracellular calcium leak, decreased reactive oxygen species (ROS), and enhanced tetanic Ca(2+) release, muscle-specific force, and exercise capacity. Taken together, these data indicate that leaky RyR1 contributes to age-related loss of muscle function.

Age-Related Differences in Muscle Power during Single-Step Balance Recovery

The purpose of this study was to investigate age-related differences in muscle power during a surrogate task of trip recovery. Participants included 10 healthy young men (19-23 years old) and 10 healthy older men (65-83). The task involved releasing participants from a forward-leaning posture. After release, participants attempted to recover their balance using a single step of the right foot. Muscle power at the hip, knee, and ankle of the stepping limb were determined from the product of joint angular velocity and joint torque. Muscle powers during balance recovery followed a relatively consistent pattern in both young and older men, and showed effects of both lean and age. Interestingly, the effects of age did not always involve smaller peak power values in the older men as expected from the well-documented loss of muscle power with aging. Older men exhibited smaller peak muscle power at the knee and larger peak muscle power at the ankle and hip compared to young men. The increases in muscle power at the ankle and hip may result from a neuromuscular adaptation aimed at improving balance recovery ability by compensating for the age-related loss of muscle function.

Lack of CuZnSOD activity: A pointer to the mechanisms underlying age-related loss of muscle function

Lack of CuZnSOD activity: A pointer to the mechanisms underlying age-related loss of muscle function