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

OBJECTIVE: Pathological, 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. DESIGN: A 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. SETTING: Preclinical laboratory study. SAMPLE SIZE: Thirty-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)]. MEASUREMENTS: Measures 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 ANALYSIS: Primary 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. RESULTS: Beta-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). CONCLUSION: KD 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.

Ketogenic Diet Improves Motor Function and Motor Unit Connectivity in Aged C57BL/6 Mice.

Objective: Pathological, 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. Design: A 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. Setting: Preclinical laboratory study. Sample size: Thirty-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)]. Measurements: Measures 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, blood samples were collected to assess blood beta-hydroxybutyrate levels. Statistical Analysis: Two-way ANOVA mixed-effects analysis (time x diet) were performed to analyze grip, rotarod, MUNE, and muscle contractility data. Results: Beta-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 (time x diet, p = 0.0030), all limb grip strength (time x diet, p = 0.0523), and rotarod latency to fall (time x diet, p = 0.0021). Mice treated with the KD intervention also demonstrated significantly greater MUNE (time x diet, p = 0.0064), but no difference in muscle contractility (time x diet, p = 0.5836) or RNS (time x diet, p = 0.9871). Conclusion: KD 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.

Anthropometry as a readily accessible health assessment of older adults.

Anthropometry (derived from the Greek Anthropos: human, and metron: measure) refers to the systematic collection, and measurement of the physical characteristics of the human body, primarily body weight, body size, and shape. Anthropometric values are closely related to genetic factors, environmental characteristics, social, and cultural conditions, lifestyle, functional status, and health. Anthropometric measurements can be used to assess risk of malnutrition, obesity, muscle wasting, increased fat mass, and maldistribution of adipose tissue. Potential modifiable factors include circumferences, skinfolds, and body weight. While are height, and the bone diameters are non-modifiable. Kinanthropometry is the study of size, shape, proportionality, composition, biological maturation, and body function, in order to understand the process of growth, exercise, sports performance, and nutrition. Aging of the population, which is associated with increased risk of chronic disease, and disability, is one of the most important demographic changes facing many countries. Anthropometric indicators are simple, portable, non-invasive, inexpensive, and easily applied measurements that can be readily applied in geriatric populations to guide preventative measures, and medical interventions in older adults.

Potential Utility of Electrical Impedance Myography in Evaluating Age-Related Skeletal Muscle Function Deficits.

Skeletal muscle function deficits associated with advancing age are due to several physiological and morphological changes including loss of muscle size and quality (conceptualized as a reduction in the intrinsic force-generating capacity of a muscle when adjusted for muscle size). Several factors can contribute to loss of muscle quality, including denervation, excitation-contraction uncoupling, increased fibrosis, and myosteatosis (excessive levels of inter- and intramuscular adipose tissue and intramyocellular lipids). These factors also adversely affect metabolic function. There is a major unmet need for tools to rapidly and easily assess muscle mass and quality in clinical settings with minimal patient and provider burden. Herein, we discuss the potential for electrical impedance myography (EIM) as a tool to evaluate muscle mass and quality in older adults. EIM applies weak, non-detectible (e.g., 400 µA), mutifrequency (e.g., 1 kHz-1 MHz) electrical currents to a muscle (or muscle group) through two excitation electrodes, and resulting voltages are measured via two sense electrodes. Measurements are fast (~5 s/muscle), simple to perform, and unaffected by factors such as hydration that may affect other simple measures of muscle status. After nearly 2 decades of study, EIM has been shown to reflect muscle health status, including the presence of atrophy, fibrosis, and fatty infiltration, in a variety of conditions (e.g., developmental growth and maturation, conditioning/deconditioning, and obesity) and neuromuscular diseases states [e.g., amyotrophic lateral sclerosis (ALS) and muscular dystrophies]. In this article, we describe prior work and current evidence of EIM's potential utility as a measure of muscle health in aging and geriatric medicine.

Profiling age-related muscle weakness and wasting: neuromuscular junction transmission as a driver of age-related physical decline.

Pathological age-related loss of skeletal muscle strength and mass contribute to impaired physical function in older adults. Factors that promote the development of these conditions remain incompletely understood, impeding development of effective and specific diagnostic and therapeutic approaches. Inconclusive evidence across species suggests disruption of action potential signal transmission at the neuromuscular junction (NMJ), the crucial connection between the nervous and muscular systems, as a possible contributor to age-related muscle dysfunction. Here we investigated age-related loss of NMJ function using clinically relevant, electrophysiological measures (single-fiber electromyography (SFEMG) and repetitive nerve stimulation (RNS)) in aged (26 months) versus young (6 months) F344 rats. Measures of muscle function (e.g., grip strength, peak plantarflexion contractility torque) and mass were assessed for correlations with physiological measures (e.g., indices of NMJ transmission). Other outcomes also included plantarflexion muscle contractility tetanic torque fade during 1-s trains of stimulation as well as gastrocnemius motor unit size and number. Profiling NMJ function in aged rats identified significant declines in NMJ transmission stability and reliability. Further, NMJ deficits were tightly correlated with hindlimb grip strength, gastrocnemius muscle weight, loss of peak contractility torque, degree of tetanic fade, and motor unit loss. Thus, these findings provide direct evidence for NMJ dysfunction as a potential mechanism of age-related muscle dysfunction pathogenesis and severity. These findings also suggest that NMJ transmission modulation may serve as a target for therapeutic development for age-related loss of physical function.