Publications

The age-related loss of skeletal muscle (sarcopenia) is a major health concern as it is associated with physical disability, metabolic impairments, and increased mortality. The coexistence of sarcopenia with obesity, termed 'sarcopenic obesity', contributes to skeletal muscle insulin resistance and the development of type 2 diabetes, a disease prevalent with advancing age. Despite this knowledge, the mechanisms contributing to sarcopenic obesity remain poorly understood, preventing the development of targeted therapeutics. This article will discuss the clinical and physiological consequences of sarcopenic obesity and propose myostatin as a potential candidate contributing to this condition. A special emphasis will be placed on examining the role of myostatin signaling in impairing both skeletal muscle growth and insulin signaling. In addition, the role of myostatin in regulating muscle-to fat cross talk, further exacerbating metabolic dysfunction in the elderly, will be highlighted. Lastly, we discuss how this knowledge has implications for the design of myostatin-inhibitor clinical trials.

The world population is ageing rapidly. As society ages, the incidence of physical limitations is dramatically increasing, which reduces the quality of life and increases healthcare expenditures. In western society,  30% of the population over 55 years is confronted with moderate or severe physical limitations. These physical limitations increase the risk of falls, institutionalization, co-morbidity, and premature death. An important cause of physical limitations is the age-related loss of skeletal muscle mass, also referred to as sarcopenia. Emerging evidence, however, clearly shows that the decline in skeletal muscle mass is not the sole contributor to the decline in physical performance. For instance, the loss of muscle strength is also a strong contributor to reduced physical performance in the elderly. In addition, there is ample data to suggest that motor coordination, excitation-contraction coupling, skeletal integrity, and other factors related to the nervous, muscular, and skeletal systems are critically important for physical performance in the elderly. To better understand the loss of skeletal muscle performance with ageing, we aim to provide a broad overview on the underlying mechanisms associated with elderly skeletal muscle performance. We start with a system level discussion and continue with a discussion on the influence of lifestyle, biological, and psychosocial factors on elderly skeletal muscle performance. Developing a broad understanding of the many factors affecting elderly skeletal muscle performance has major implications for scientists, clinicians, and health professionals who are developing therapeutic interventions aiming to enhance muscle function and/or prevent mobility and physical limitations and, as such, support healthy ageing.

In older adults, the loss of muscle strength (dynapenia) and the loss of muscle mass (sarcopenia) are important contributors to the loss of physical function. We sought to investigate dynapenia, sarcopenia, and the loss of motor unit function in aging mice. C57BL/6J mice were analyzed with cross-sectional (males: 3 vs. 27 months; males and females: 8 vs. 12 vs. 20 months) and longitudinal studies (males: 10-25 months) using in vivo electrophysiological measures of motor unit connectivity (triceps surae compound muscle action potential and motor unit number estimation), in vivo measures of plantar flexion torque, magnetic resonance imaging of hind limb muscle volume, and grip strength. Compound muscle action potential amplitude, motor unit number estimation, and plantar flexion torque were decreased at 20 months. In contrast, grip strength was reduced at 24 months. Motor unit number estimates correlated with muscle torque and hind limb muscle volume. Our results demonstrate that the loss of motor unit connectivity is an early finding in aging male and female mice and that muscle size and contractility are both associated with motor unit number.

Understanding mechanisms of fatigue of the trunk extensors is important because fatigue is a major factor in predicting incidence of low back pain, but few studies have examined trunk extensor fatigue muscles using differing load types and measured the amplitude and frequency domain of the electromyographic signal to explain these differences. Sixteen healthy participants performed position- and force-matching fatigue tasks in a modified Sorensen test position. Time to task failure was significantly longer during the position-matching task compared to force-matching task (58.3 +/- 6.6 min vs. 36.1 +/- 5.4 min). This finding is the opposite of that commonly reported for the appendicular muscle, but the mean power frequency shifts and muscle activation patterns of the trunk and hip extensors did not explain this difference. The mean power frequency shifts and muscle activation patterns of the trunk and hip extensors did not explain this difference. The greater time to task failure during the position-matching task may reflect adaptation of the trunk extensor muscles to optimize maintaining specific joint angles more so than specific loads.

Evidence suggests that paternal diet can predispose offspring to metabolic dysfunction. Despite this knowledge, little is known regarding the effects of paternal high-fat feeding on offspring insulin sensitivity. The purpose of this study was to investigate for the first time the effects of paternal high-fat feeding on whole-body and skeletal muscle insulin action in young and adult offspring. At 4 weeks of age, founder C57BL6/N males (F0) were fed a high-fat diet or control diet for 12 weeks and then bred with females on a control diet. Offspring (F1) were euthanized at 6 weeks, 6 months, or 12 months and insulin-stimulated insulin signaling was measured ex vivo in isolated soleus muscle. At 6 weeks of age, paternal high fat offspring (HFO) had enhanced whole-body insulin sensitivity (35%, P 0.05), as well as, increased insulin-stimulated skeletal muscle phosphorylation of Akt threonine 308 (70%, P 0.05) and AS160 threonine 642 (80%, P 0.05) compared to paternal control fed offspring (CFO), despite both offspring groups consuming standard chow. At 6 months of age, HFO had increased percent body fat compared to CFO (74%, P 0.005) and whole-body and skeletal muscle insulin signaling normalized to CFO. Body fat was inversely related with insulin signaling in HFO, but not CFO. These findings suggest that paternal high-fat feeding contributes to enhanced whole-body and skeletal muscle insulin sensitivity in HFO early in life; however, these benefits are lost by early adulthood, potentially due to premature increases in body fat.

BACKGROUND: Low back pain (LBP) is one of the most common reasons for seeking medical care. Manipulative therapies are a common treatment for LBP. Few studies have compared the effectiveness of different types of manipulative therapies. Moreover, the physiologic mechanisms underlying these treatments are not fully understood. Herein, we present the study protocol for The Researching the Effectiveness of Lumbar Interventions for Enhancing Function Study (The RELIEF Study). METHODS AND STUDY DESIGN: The RELIEF Study is a Phase II RCT with a nested mechanistic design. It is a single-blinded, sham-controlled study to test the mechanisms and effectiveness of two manual therapy techniques applied to individuals (n = 162; 18-45 years of age) with chronic LBP. The clinical outcome data from the mechanistic component will be pooled across experiments to permit an exploratory Phase II RCT investigating the effectiveness. Participants will be randomized into one of three separate experiments that constitute the mechanistic component to determine the muscular, spinal, and cortical effects of manual therapies. Within each of these experimental groups study participants will be randomly assigned to one of the three treatment arms: 1) spinal manipulation, 2) spinal mobilization, or 3) sham laser therapy. Treatments will be delivered twice per week for 3-weeks. DISCUSSION: This data from this will shed light on the mechanisms underlying popular treatments for LBP. Additionally, the coupling of this basic science work in the context of a clinical trial will also permit examination of the clinical efficacy of two different types of manipulative therapies.

There are a large number of age-related changes that occur in the tissues that make up the musculoskeletal system. Many of these changes contribute to the most pervasive chronic conditions seen in older adults. In fact, musculoskeletal disorders are the most common cause of chronic disability in late life. This is attributable both to the prevalence of disorders affecting the musculoskeletal system as well as the central role of the musculoskeletal system for daily function for independent living. Despite the prevalence of musculoskeletal disorders, however, there is still much to learn about the pathogenesis of these disorders, including the role of aging, and the interactive role of physical inactivity, in their development.

This chapter reviews aging in each of the major components of the musculoskeletal system including the neuromuscular system, which includes a detailed discussion on sarcopenia (age-related muscle atrophy) and dynapenia (age-related muscle weakness), as well as cartilage, ligaments and tendons, and intervertebral disks (refer to Table 113-1). Although bone is a key player in the musculoskeletal system, aging changes in this tissue are discussed in more detail in Chapter 118.

The purpose of this study was to develop a novel magnetic resonance imaging (MRI)-based modeling technique for measuring intervertebral displacements. Here, we present the measurement bias and reliability of the developmental work using a porcine spine model. Porcine lumbar vertebral segments were fitted in a custom-built apparatus placed within an externally calibrated imaging volume of an open-MRI scanner. The apparatus allowed movement of the vertebrae through pre-assigned magnitudes of sagittal and coronal translation and rotation. The induced displacements were imaged with static (T(1)) and fast dynamic (2D HYCE S) pulse sequences. These images were imported into animation software, in which these images formed a background 'scene'. Three-dimensional models of vertebrae were created using static axial scans from the specimen and then transferred into the animation environment. In the animation environment, the user manually moved the models (rotoscoping) to perform model-to-'scene' matching to fit the models to their image silhouettes and assigned anatomical joint axes to the motion-segments. The animation protocol quantified the experimental translation and rotation displacements between the vertebral models. Accuracy of the technique was calculated as 'bias' using a linear mixed effects model, average percentage error and root mean square errors. Between-session reliability was examined by computing intra-class correlation coefficients (ICC) and the coefficient of variations (CV). For translation trials, a constant bias (beta(0)) of 0.35 (+/-0.11) mm was detected for the 2D HYCE S sequence (p=0.01). The model did not demonstrate significant additional bias with each mm increase in experimental translation (beta(1)Displacement=0.01mm; p=0.69). Using the T(1) sequence for the same assessments did not significantly change the bias (p>0.05). ICC values for the T(1) and 2D HYCE S pulse sequences were 0.98 and 0.97, respectively. For rotation trials, a constant bias (beta(0)) of 0.62 (+/-0.12) degrees was detected for the 2D HYCE S sequence (p0.01). The model also demonstrated an additional bias (beta(1)Displacement) of 0.05 degrees with each degree increase in the experimental rotation (p0.01). Using T(1) sequence for the same assessments did not significantly change the bias (p>0.05). ICC values for the T(1) and 2D HYCE S pulse sequences were recorded 0.97 and 0.91, respectively. This novel quasi-static approach to quantifying intervertebral relationship demonstrates a reasonable degree of accuracy and reliability using the model-to-image matching technique with both static and dynamic sequences in a porcine model. Future work is required to explore multi-planar assessment of real-time spine motion and to examine the reliability of our approach in humans.