Eli Carmeli

Matrix metalloproteinases and skeletal muscle: A brief review

Matrix metalloproteinases (MMPs) are a family of zinc‐ dependent proteolytic enzymes that function mainly in the extracellular matrix, where they contribute to the development, functioning, and pathology of a wide range of tissues. This mini‐review describes the MMPs and tissue inhibitors of MMPs (TIMPs) in skeletal muscle, and considers their involvement in muscle development, ischemia, myonecrosis, angiogenesis, denervation, exercise‐induced injuries, disuse atrophy, muscle repair and regeneration, and inflammatory myopathies and dystrophies. Despite the very limited information currently available on MMPs and their inhibitors in skeletal muscle, it is becoming increasingly clear that they have important physiological functions in maintenance of the integrity and homeostasis of muscle fibers and of the extracellular matrix. Understanding the roles of MMPs and TIMPs may lead to the development of new drug‐related treatments for various muscle disorders based on suppression or upregulation of their expression. Muscle Nerve 29: 191–197, 2004

Exercise and immobilization in aging animals: The involvement of oxidative stress and NF-κB activation

In the early 1980s, the concept of threshold of age in exercise and aging was proposed. In several studies it was shown that subjecting young animals to short periods of moderate to intense exercise improved the biochemical and morphological status of their skeletal muscles. This was not the case for old animals subjected to the same exercise regimens. Thus, by measuring several muscle energy-providing enzymes as well as antioxidant enzymes it was demonstrated that their levels and activities increased in young animals postexercise, while in old animals reduced activity of these enzymes was found on completion of the training. However, old animals that started training in young and middle age were still capable of improving their muscle condition as a result of exercise, as long as the onset of training was below a specific age threshold. In the following years, it was shown that intense physical exercise in young humans and animals is accompanied by elevation of oxidative stress parameters in muscles and other organs. Specifically, strenuous training of animals led to increased protein oxidation as measured by protein carbonyl accumulation in muscles, which could be attenuated by the administration of vitamin E. Nuclear factor kappaB (NF-kappaB) is a redox-sensitive transcription factor responsive to closely related reactive oxygen species (ROS) and reactive nitrogen species (RNS) redox cascades. Its involvement in exercise and immobilization has been demonstrated in several studies, indicating that these conditions may lead to inflammatory responses and to oxidative damage to tissues. Indeed, recent studies have revealed that NF-kappaB is involved in inflammatory responses that may result in muscle protein degradation. Additional studies have also demonstrated that the pattern and type of the NF-kappaB activation pathway vary between muscles of young and old animals subjected to limb immobilization for several weeks. This indicates that NF-kappaB may play a crucial role in the regulation of both inflammatory processes and protein turnover and degradation in muscles of old animals. Thus, the modulation of NF-kappaB activity in muscles of old animals by specific inhibitors may provide a means to retard muscle damage and protein degradation under conditions of immobilization.

The influence of early aerobic training on the functional capacity in patients with cerebrovascular accident at the subacute stage.

OBJECTIVE To investigate the effect of early aerobic training on the aerobic and functional abilities of patients in the subacute stage of cerebrovascular accident (CVA). DESIGN Randomized controlled trial. SETTING Rehabilitation unit in Israel. PARTICIPANTS Ninety-two patients who had a first CVA were randomly assigned to an exercise-training group or to a control group. INTERVENTION Aerobic training with a leg cycle ergometer for 8 weeks. MAIN OUTCOME MEASURES Workload, exercise time, resting and submaximal blood pressure and heart rate, and functional abilities. RESULTS A trend toward improvement was found in all aerobic parameters for the experimental group, but only heart rate at rest (P=.02), workload, and work time (P<.01) improved significantly. A trend for improvement was also found in all parameters of function for the experimental group, but only stair climbing was significantly better (P<.01). An interaction (95% confidence interval, 1.7-17.21) was found between age and aerobic training on walking distance. Although no significant effect was found in the group of younger patients (aged <65y), a significant difference in favor of training was noted in the group of older patients. CONCLUSIONS Patients with CVA in the subacute stage improved some of their aerobic and functional abilities after submaximal aerobic training.

High intensity exercise increases expression of matrix metalloproteinases in fast skeletal muscle fibres.

Metalloproteinases (MMPs) are proteolytic enzymes that function in the extracellular matrix to degrade connective tissues. While it is clear that exercise‐induced injury in skeletal muscle promotes increased expression of MMPs, the relationship between exercise intensity and expression of MMPs in muscles is unknown. These experiments tested the hypothesis that exercise‐induced expression of matrix metalloproteinases (MMP‐2 and MMP‐9) is dose‐dependent such that high‐intensity endurance exercise increases MMP expression whereas low‐intensity endurance exercise will not promote MMP expression in skeletal muscles. Female rats (4 months old) completed 2 weeks of treadmill running at either low (18 m min−1; ∼50% maximum oxygen consumption rate ) or high intensity (32 m min−1; ∼70% ; up to 50 min day−1). Non‐running, sedentary animals served as controls. Muscle mRNA and protein levels of MMP‐2 and MMP‐9 were assessed in gastrocnemius, quadriceps and soleus muscles by reverse transcriptase‐polymerase chain reaction and Western blotting, respectively. Results indicate that exercise did not alter MMP‐9 in any of these skeletal muscles. Further, our data reveal that low‐intensity exercise did not alter the expression of MMP‐2 in any of the muscles investigated. In contrast, high‐intensity exercise increased both mRNA and protein levels of MMP‐2 in skeletal muscles containing a high percentage of fast type II fibres (i.e. gastronemius and superficial quadriceps). These results support the hypothesis that high‐intensity exercise is required to promote the expression of MMP‐2 in skeletal muscles and that the influence of exercise on MMP‐2 expression is dominant in muscles containing a high percentage of fast fibres.

The Physiology and Biochemistry of Skeletal Muscle Atrophy as a Function of Age

Abstract The skeletal muscles are an important entity in the proper function of aging animals and humans. Studies have shown that until humans are 60-70 years old, age-related changes in muscle function and structure are relatively small, while after 70 years, these alterations are accelerated considerably. Factors responsible for the “aging” of skeletal muscles are complex and include intrinsic biochemical changes in muscle metabolism, changes in the distribution and size of muscle fibers, and a general loss of muscle mass. In addition, other factors like the control of muscle contraction by the motor neural system and the influence of external conditions such as exercise, immobility, nutrition and others may also contribute to the age-related decrease in muscle functions. Studies have shown that with age there is some loss of peripheral motor neurons, reduction in the number of motor units, alterations in the neuromuscular junctions, and selective denervation of Type II muscle fibers. These findings led to the concept of denervation atrophy of skeletal muscles as one of the major mechanisms for muscle degeneration in old age. However, it should be emphasized that the extent of age-related changes varies from muscle to muscle, and some do not seem to be affected by age. For example, it has been shown recently, in animal studies, that weight-bearing muscles are much more susceptible to senescent processes than non-weight-bearing muscles. More work is needed to clarify the contributions of the various factors, especially the role of muscle training in alleviating the symptoms of age-related muscle atrophy.

Muscle Strength and Mass of Lower Extremities in Relation to Functional Abilities in Elderly Adults

Background: Functional and physiological declines in advancing age may be significant limiting factors in reduced physical activity. Sarcopenia of aging, as a normative process or disease, cannot entirely explain reduced physical activity in the elderly. Objective: The purpose of the study was to investigate the relationship between muscle loss and reduction in functional abilities in elderly adults and also to determine whether an exercise program can improve functional performance and muscle quality. Methods: Anthropometric measurements and sensorimotor testing were conducted on 28 volunteers (12 men and 16 women, 82.7 ± 2.4 years of age) who were permanent residents in a skilled nursing facility. Twenty-nine elderly adults (79.3 ± 3.5 years of age) served as a control, nonexercising group. Anthropometric measurements included: weight, height, body fat, and thigh circumference. The muscle strength was tested with a medical isokinetic system. We assessed two sensorimotor functions including a ‘timed up-and-go’ test and a 3-min distance walking test. The institutionalized participants undertook an exercise training program lasting 12 weeks. Results: No significant changes were observed in thigh circumference, body weight, or percentage of body fat in either gender as a result of the exercise training. An improvement in muscle strength was noticed in 82% of the relatively younger group (79–83 years of age) under a slow voluntary contraction at 60°/s (p < 0.05). Post-training results showed a significant improvement in performance in the two sensorimotor tests (p < 0.05). The correlation coefficients between muscle strength and functional ability were weak: r = 0.60 and r = 0.57 for males and females, respectively. Conclusions: This study confirmed the positive effects of an exercise program on functional performance in older adults. The improvement in functional abilities did not correlate with muscle strength, body weight, or body fat.

Reliability and validity of the modified functional reach test at the sub-acute stage post-stroke

Objectives. The first aim of this study was to evaluate the within-session reliability of sitting balance measures by assessing forward and lateral reach while sitting in both healthy subjects and patients post- stroke. The second aim was to evaluate the ability to document change in reaching while sitting over time in patients post-stroke. The third aim was to compare sitting balance results by the modified functional reach test (MFRT) to the Balance Master (BM), motor and function assessments. Design. Data were collected on two occasions: Two to three weeks post-event and again six weeks later. On each occasion within-session reliability was tested using the intra-class correlations (ICC). The tests were performed three times; the second and third attempts were compared in order to test the within-session reliability. For assessing the concurrent validity, the MFRT results were compared with the BM results, Stroke Assessment Scale (SAS) and the Functional Independence Measure (FIM) score using Pearson correlations. Setting. In-patient rehabilitation department. Participants. Patients after a first ischemic stroke 14 – 21 days post-event were recruited from the inpatient rehabilitation department at Hadassah University Hospital, Jerusalem, Israel. Excluded were patients with brain stem lesions and/or bilateral signs or hemorrhagic events as diagnosed by Computerized Tomography, patients with Mini-Mental State Examination < 20, those who were not able to sit unsupported for 10 sec and those who could stand without support for more than 30 sec. Main Outcome Measures. The MFRT, performed while sitting in forward and sideward directions. Results. The MFRT in all directions on both occasions exhibited high reliability (intra-class correlation coefficient range, 0.90 – 0.97). The responsiveness to the paretic side was high (effect size 0.80) and moderate for the forward and non-paretic side (effect size 0.57 – 0.60). A significant moderate correlation was found between MFRT and BM on both occasions. Conclusion. The MFRT while sitting can be reliably measured and may serve as a useful outcome measure in individuals with stroke 2 – 8 weeks post-event.

A quantitative somatosensory testing of pain threshold in individuals with mental retardation

&NA; The commonly held view, mainly based on behavioral observations, is that individuals with mental retardation (MR) have a decreased sensitivity to pain. However, the sensitivity to noxious stimuli was not systematically measured in these individuals. For this purpose we developed an experimental protocol with which we trained individuals with mild MR (unspecified MR and Downs syndrome) in heat‐pain threshold (HPT) measurement on the hand, and then performed the measurement using both the method of limits (MLI) which relies on reaction time (RT) and the method of levels (MLE) which is RT‐free. This allowed for an indirect assessment of the RT and conduction velocity (CV) of these individuals. We found that HPT in individuals with unspecified MR (41.23±1.86 °C) and Downs syndrome (40.96±2.93 °C) was significantly lower than that of controls (42.86±2.42 °C) when measured with the MLE (P<0.05). With the MLI no significant differences in HPT were found between the groups. However, the RT and CV values of individuals with unspecified MR and Downs syndrome were significantly lower compared to controls (e.g. mean RT of 1.86 and 2.55 compared to 1.2 s, respectively, P<0.01). From this work it would appear that individuals with MR are not only pain‐sensitive, but also more sensitive to heat‐pain than normal. It is suggested that computerized quantitative testing of pain threshold is feasible in individuals with MR preferably by using RT‐free methods (e.g. the MLE) due to the low RT and CV values exhibited by them.

Review ArticleExercise and immobilization in aging animals: The involvement of oxidative stress and NF-κB activation

In the early 1980s, the concept of threshold of age in exercise and aging was proposed. In several studies it was shown that subjecting young animals to short periods of moderate to intense exercise improved the biochemical and morphological status of their skeletal muscles. This was not the case for old animals subjected to the same exercise regimens. Thus, by measuring several muscle energy-providing enzymes as well as antioxidant enzymes it was demonstrated that their levels and activities increased in young animals postexercise, while in old animals reduced activity of these enzymes was found on completion of the training. However, old animals that started training in young and middle age were still capable of improving their muscle condition as a result of exercise, as long as the onset of training was below a specific age threshold. In the following years, it was shown that intense physical exercise in young humans and animals is accompanied by elevation of oxidative stress parameters in muscles and other organs. Specifically, strenuous training of animals led to increased protein oxidation as measured by protein carbonyl accumulation in muscles, which could be attenuated by the administration of vitamin E. Nuclear factor kappaB (NF-kappaB) is a redox-sensitive transcription factor responsive to closely related reactive oxygen species (ROS) and reactive nitrogen species (RNS) redox cascades. Its involvement in exercise and immobilization has been demonstrated in several studies, indicating that these conditions may lead to inflammatory responses and to oxidative damage to tissues. Indeed, recent studies have revealed that NF-kappaB is involved in inflammatory responses that may result in muscle protein degradation. Additional studies have also demonstrated that the pattern and type of the NF-kappaB activation pathway vary between muscles of young and old animals subjected to limb immobilization for several weeks. This indicates that NF-kappaB may play a crucial role in the regulation of both inflammatory processes and protein turnover and degradation in muscles of old animals. Thus, the modulation of NF-kappaB activity in muscles of old animals by specific inhibitors may provide a means to retard muscle damage and protein degradation under conditions of immobilization.

Effect of physical therapy on muscle strength, respiratory muscles and functional parameters in patients with intensive care unit-acquired weakness.

The aim of this study was to evaluate the effect of an intensive physical therapy protocol in patients who contract ‘intensive care unit‐acquired weakness’ (ICUAW), in terms of muscle strength, breathing and functional indices.