Richard K. Shields

mRNA Expression Signatures of Human Skeletal Muscle Atrophy Identify a Natural Compound that Increases Muscle Mass

Skeletal muscle atrophy is a common and debilitating condition that lacks a pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs that were regulated by fasting in both human and mouse muscle, and 29 mRNAs that were regulated by both fasting and spinal cord injury in human muscle. We used these two unbiased mRNA expression signatures of muscle atrophy to query the Connectivity Map, which singled out ursolic acid as a compound whose signature was opposite to those of atrophy-inducing stresses. A natural compound enriched in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling and inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly, ursolic acids effects on muscle were accompanied by reductions in adiposity, fasting blood glucose, and plasma cholesterol and triglycerides. These findings identify a potential therapy for muscle atrophy and perhaps other metabolic diseases.

Muscle and bone plasticity after spinal cord injury: Review of adaptations to disuse and to electrical muscle stimulation

The paralyzed musculoskeletal system retains a remarkable degree of plasticity after spinal cord injury (SCI). In response to reduced activity, muscle atrophies and shifts toward a fast-fatigable phenotype arising from numerous changes in histochemistry and metabolic enzymes. The loss of routine gravitational and muscular loads removes a critical stimulus for maintenance of bone mineral density (BMD), precipitating neurogenic osteoporosis in paralyzed limbs. The primary adaptations of bone to reduced use are demineralization of epiphyses and thinning of the diaphyseal cortical wall. Electrical stimulation of paralyzed muscle markedly reduces deleterious post-SCI adaptations. Recent studies demonstrate that physiological levels of electrically induced muscular loading hold promise for preventing post-SCI BMD decline. Rehabilitation specialists will be challenged to develop strategies to prevent or reverse musculoskeletal deterioration in anticipation of a future cure for SCI. Quantifying the precise dose of stress needed to efficiently induce a therapeutic effect on bone will be paramount to the advancement of rehabilitation strategies.

Health related quality of life in patients with total hip or knee replacement.

OBJECTIVE The Quality of Well Being index (QWB) and the SF-36 are questionnaires that have received widespread use in outcomes research. The relationship between the QWB index and the SF-36 was studied in patients receiving total hip or knee replacement because of primary osteoarthritis, and the health status of these individuals was contrasted to that of the general population. DESIGN The QWB and SF-36 were both administered preoperatively and postoperatively and at 3 and 6 months in individuals with hip or knee replacement. SETTING A primary care university teaching hospital. PATIENTS Forty-three subjects with an age range of 30 to 78 years (mean 58 yrs, SD 10.6) who received total joint replacement, either hip or knee. RESULTS The change in the QWB at 3 and 6 months after a total hip replacement or total knee replacement was most associated with the change in general health (.50), bodily pain (.72), and vitality (.62) of the SF-36. Both tools (QWB, SF-36) demonstrated similar levels of responsiveness and the scores were lower than the scores from the general population. CONCLUSION The summary score of the QWB and various health concepts of the SF-36 respond similarly after joint replacement from osteoarthritis. The relationship between the change in the QWB and SF-36 depends on the time after surgery (3 vs. 6 months) and the type of joint replacement (knee vs. hip).

Musculoskeletal Adaptations in Chronic Spinal Cord Injury: Effects of Long-term Soleus Electrical Stimulation Training

Objective. The purpose of this study was to determine whether long-term electrical stimulation training of the paralyzed soleus could change this muscle’s physiological properties (torque, fatigue index, potentiation index, torque-time integral) and increase tibia bone mineral density. Methods. Four men with chronic (>2 years) complete spinal cord injury (SCI; American Spinal Injury Association classification A) trained 1 soleus muscle using an isometric plantar flexion electrical stimulation protocol. The untrained limb served as a within-subject control. The protocol involved ~ 30 minutes of training each day, 5 days a week, for a period of 6 to 11 months. Mean compliance over 11 months of training was 91% for 3 subjects. A fourth subject achieved high compliance after only 5 months of training. Mean estimated compressive loads delivered to the tibia were ~110% of body weight. Over the 11 months of training, the muscle plantar flexion torque, fatigue index, potentiation index, and torque-time integral were evaluated periodically. Bone mineral density (dual-energy x-ray absorptiometry) was evaluated before and after the training program. Results.The trained limb fatigue index, potentiation index, and torque-time integral showed rapid and robust training effects (P <.05). Soleus electrical stimulation training yielded no changes to the proximal tibia bone mineral density, as measured by dual-energy x-ray absorptiometry. The subject with low compliance experienced fatigue index and torque-time integral improvements only when his compliance surpassed 80%. In contrast, his potentiation index showed adaptations even when compliance was low. Conclusions. These findings highlight the persistent adaptive capabilities of chronically paralyzed muscle but suggest that preventing musculoskeletal adaptations after SCI may be more effective than reversing changes in the chronic condition.

Neuromuscular Control of the Knee During a Resisted Single-Limb Squat Exercise

Background Closed kinetic chain exercises such as single-limb squats are preferred for knee rehabilitation. A complete understanding of the neuromuscular control of the knee during the single-limb squat is essential to increase the efficiency of rehabilitation programs. Hypothesis Performing a controlled single-limb squat with resistance to knee flexion and extension will increase the coactivation of the hamstring muscle group, thus reducing the quadriceps/hamstrings ratio. Study Design Descriptive laboratory study. Methods A total of 15 healthy human subjects (7 women, 8 men) performed controlled single-limb squats in a custom mechanical device that provided resistance to both flexion and extension. Subjects performed the task at 3 levels of resistance, set as a percentage of body weight. Surface electromyographic recordings from 7 muscles (gluteus medius, rectus femoris, vastus medialis oblique, vastus lateralis, biceps femoris, semitendinosus, and medial gastrocnemius) were collected during the task. Results Biceps femoris activity during knee flexion increased from approximately 12% maximum voluntary isometric contractions during low resistance (0% body weight) to approximately 27% maximum voluntary isometric contractions during high resistance (8% body weight). Although the quadriceps had greater activity than the hamstrings at all levels of resistance, the quadriceps/hamstrings ratio declined significantly with resistance (F2,27 = 29.05; P=. 012) from 3.0 at low resistance to 2.32 at the highest resistance. Conclusions Performing controlled resisted single-limb squats may help to simultaneously strengthen the quadriceps and facilitate coactivation of the hamstrings, thus reducing anterior tibial shear forces. The coactivation may also increase the dynamic control of the knee joint. Clinical Relevance The typical single-limb squat exercise performed in the clinic does not usually control for bidirectional resistance and knee joint excursion. As seen in this study, controlled single-limb squats at increased levels of resistance help to increase the coactivation of the hamstring muscles, which is essential to optimize neuromuscular control of the knee.

Electrically induced muscle contractions influence bone density decline after spinal cord injury

Study Design. Longitudinal repeated-measures; within-subject control. Objective. We examined the extent to which an isometric plantar flexion training protocol attenuates bone loss longitudinally after SCI. Summary of Background Data. After spinal cord injury (SCI), bone mineral density (BMD) of paralyzed extremities rapidly declines, likely because of loss of mechanical loading of bone via muscle contractions. Methods. Six individuals with complete paralysis began a 3-year unilateral plantar flexor muscle activation program within 4.5 months after SCI. The opposite limb served as a control. Compliance with recommended dose was >80%. Tibia compressive force was >140% of body weight. Results. Bilateral hip and untrained tibia BMD declined significantly over the course of the training. Lumbar spine BMD showed minimal change. Percent decline in BMD (from the baseline condition) for the trained tibia (∼10%) was significantly less than the untrained tibia (∼25%) (P < 0.05). Trained limb percent decline in BMD remained steady over the first 1.5 years of the study (P < 0.05). Conclusions. Compressive loads of ∼1 to 2 times body weight, induced by muscle contractions, partially prevent the loss of BMD after SCI. Future studies should establish dose-response curves for attenuation of bone loss after SCI.

Dose estimation and surveillance of mechanical loading interventions for bone loss after spinal cord injury.

Background and Purpose: The interpretation of the results of previous anti-osteoporosis interventions after spinal cord injury (SCI) is undermined by incomplete information about the intervention dose or patient adherence to dose requirements. Rehabilitation research as a whole traditionally has struggled with these same issues. The purpose of this case report is to offer proof of the concepts that careful dose selection and surveillance of patient adherence should be integral components in rehabilitation interventions. Case Description: A 21-year-old man with T4 complete paraplegia (7 weeks) enrolled in a unilateral soleus muscle electrical stimulation protocol. Compressive loads applied to the tibia approximated 1.4 times body weight. Over 4.8 years of home-based training, data logging software provided surveillance of adherence. Soleus muscle torque and fatigue index adaptations to training as well as bone mineral density (BMD) adaptations in the distal tibia were measured. Outcomes: The patient performed nearly 8,000 soleus muscle contractions per month, with occasional fluctuations. Adherence tracking permitted intervention when adherence fell below acceptable values. The soleus muscle torque and fatigue index increased rapidly in response to training. The BMD of the untrained tibia declined approximately 14% per year. The BMD of the trained tibia declined only approximately 7% per year. The BMD was preferentially preserved in the posterior half of the tibia; this region experienced only a 2.6% annual decline. Discussion: Early administration of a load intervention, careful estimation of the loading dose, and detailed surveillance of patient adherence aided in the interpretation of a patients adaptations to a mechanical load protocol. These concepts possess wider applicability to rehabilitation research and should be emphasized in future physical therapy investigations.

AN ELECTROMYOGRAPHIC COMPARISON OF ABDOMINAL MUSCLE SYNERGIES DURING CURL AND DOUBLE STRAIGHT LEG LOWERING EXERCISES WITH CONTROL OF THE PELVIC POSITION

Study Design. This prospective study evaluated the abdominal muscle activity during the isometric bent knee curl and double straight leg lowering exercise. Objectives. To compare the magnitude of the electromyographic activity across the curl and double straight leg lowering exercise and determine if the muscle synergies were specific to a given exercise. Summary of Background Data. Abdominal muscle strengthening exercises are frequently recommended in the prevention and rehabilitation of individuals with low back pain. Previous studies comparing the curl exercise with the double straight leg lowering exercise did not support the notion that the double straight leg lowering exercise is more demanding on the abdominal muscles. No previous study examined these two exercises while maintaining a constant pelvic position. Methods. Fifteen male subjects had the electromyographic activity of the rectus abdominis, the external oblique, and the internal oblique abdominal muscles evaluated during the curl and double straight leg lowering exercise. The same position of the posterior pelvic tilt was maintained between each exercise using feedback from an electrogoniometer attached to the pelvis. Results. The double straight leg lowering exercise resulted in significantly greater activation of the abdominal muscles compared with the curl. Two abdominal muscle synergies emerged during the double straight leg lowering exercise: synergy I exhibited high rectus abdominis, high external oblique, and low internal oblique muscle activity, whereas synergy II exhibited low rectus abdominis, high external oblique, and high internal oblique. Conclusions. The results support the use of the double straight leg lowering with the posterior pelvic tilt for achieving greater abdominal muscle coactivation in an exercise program.

Brief paper: Identification of a modified Wiener-Hammerstein system and its application in electrically stimulated paralyzed skeletal muscle modeling

Electrical muscle stimulation demonstrates potential for restoring functional movement and preventing muscle atrophy after spinal cord injury (SCI). Control systems used to optimize delivery of electrical stimulation protocols depend upon mathematical models of paralyzed muscle force outputs. While accurate, the Hill-Huxley-type model is very complex, making it difficult to implement for real-time control. As an alternative, we propose a modified Wiener-Hammerstein system to model the paralyzed skeletal muscle dynamics under electrical stimulus conditions. Experimental data from the soleus muscles of individuals with SCI was used to quantify the model performance. It is shown that the proposed Wiener-Hammerstein system is at least comparable to the Hill-Huxley-type model. On the other hand, the proposed system involves a much smaller number of unknown coefficients. This has substantial advantages in identification algorithm analysis and implementation including computational complexity, convergence and also in real time model implementation for control purposes.

The effects of fatigue on the torque-frequency curve of the human paralysed soleus muscle.

An advanced understanding of the torque-generating properties of the chronically paralysed soleus muscle may be instrumental in developing improved methods to activate human paralysed muscle. We established the shape of the torque-frequency curve before and after fatigue of the human paralysed soleus muscle. After fatigue, the normalized torque-frequency curve was shifted to the right, suggesting a higher frequency was required to generate the same relative torque. Low frequency fatigue (LFF) consisting of reduced torques at low frequencies and normal torques at higher frequencies was demonstrated. Conversely, the acutely paralysed soleus muscle was found to be fatigue-resistant and showed no shift in the torque-frequency curve. The muscle activation history (potentiation), LFF, and changing contractile speeds may affect the torque-frequency curve after fatigue. These factors may also play an important role in the development of optimal methods to activate paralysed muscle to attenuate fatigue.