Mechanisms of exercise as a preventative measure to muscle wasting.

Skeletal muscle is the most abundant tissue in healthy individuals and it has important roles in health beyond voluntary movement. The overall mass and energy requirements of skeletal muscle require it to be metabolically active and flexible to multiple energy substrates. The tissue has evolved to be largely load dependent and it readily adapts in a number of positive ways to repetitive overload, such as various forms of exercise training. However, unloading from extended bed rest and/or metabolic derangements in response to trauma, acute illness, or severe pathology, commonly results in rapid muscle wasting. Decline in muscle mass contributes to multimorbidity, reduces function, and exerts a substantial, negative impact on the quality of life. The principal mechanisms controlling muscle mass have been well described and these cellular processes are intricately regulated by exercise. Accordingly, exercise has shown great promise and efficacy in preventing or slowing muscle wasting through changes in molecular physiology, organelle function, cell signaling pathways, and epigenetic regulation. In this review, we focus on the role of exercise in altering the molecular landscape of skeletal muscle in a manner that improves or maintains its health and function in the presence of unloading or disease.epigenetics; exercise; muscle wasting; resistance training; skeletal muscle.

Implantation of muscle satellite cells overexpressing myogenin improves denervated muscle atrophy in rats.

This study evaluated the effect of muscle satellite cells (MSCs) overexpressing myogenin (MyoG) on denervated muscle atrophy. Rat MSCs were isolated and transfected with the MyoG-EGFP plasmid vector GV143. MyoG-transfected MSCs (MTMs) were transplanted into rat gastrocnemius muscles at 1 week after surgical denervation. Controls included injections of untransfected MSCs or the vehicle only. Muscles were harvested and analyzed at 2, 4, and 24 weeks post-transplantation. Immunofluorescence confirmed MyoG overexpression in MTMs. The muscle wet weight ratio was significantly reduced at 2 weeks after MTM injection (67.17±6.79) compared with muscles injected with MSCs (58.83±5.31) or the vehicle (53.00±7.67; t=2.37, P=0.04 and t=3.39, P=0.007, respectively). The muscle fiber cross-sectional area was also larger at 2 weeks after MTM injection (2.63×10³±0.39×10³) compared with MSC injection (1.99×10³±0.58×10³) or the vehicle only (1.57×10³±0.47×10³; t=2.24, P=0.049 and t=4.22, P=0.002, respectively). At 4 and 24 weeks post-injection, the muscle mass and fiber cross-sectional area were similar across all three experimental groups. Immunohistochemistry showed that the MTM group had larger MyoG-positive fibers. The MTM group (3.18±1.13) also had higher expression of MyoG mRNA than other groups (1.41±0.65 and 1.03±0.19) at 2 weeks after injection (t=2.72, P=0.04). Transplanted MTMs delayed short-term atrophy of denervated muscles. This approach can be optimized as a novel stand-alone therapy or as a bridge to surgical re-innervation of damaged muscles.

Implantation of muscle satellite cells overexpressing myogenin improves denervated muscle atrophy in rats

This study evaluated the effect of muscle satellite cells (MSCs) overexpressing myogenin (MyoG) on denervated muscle atrophy. Rat MSCs were isolated and transfected with the MyoG-EGFP plasmid vector GV143. MyoG-transfected MSCs (MTMs) were transplanted into rat gastrocnemius muscles at 1 week after surgical denervation. Controls included injections of untransfected MSCs or the vehicle only. Muscles were harvested and analyzed at 2, 4, and 24 weeks post-transplantation. Immunofluorescence confirmed MyoG overexpression in MTMs. The muscle wet weight ratio was significantly reduced at 2 weeks after MTM injection (67.17±6.79) compared with muscles injected with MSCs (58.83±5.31) or the vehicle (53.00±7.67; t=2.37, P=0.04 and t=3.39, P=0.007, respectively). The muscle fiber cross-sectional area was also larger at 2 weeks after MTM injection (2.63×103±0.39×103) compared with MSC injection (1.99×103±0.58×103) or the vehicle only (1.57×103±0.47×103; t=2.24, P=0.049 and t=4.22, P=0.002, respectively). At 4 and 24 weeks post-injection, the muscle mass and fiber cross-sectional area were similar across all three experimental groups. Immunohistochemistry showed that the MTM group had larger MyoG-positive fibers. The MTM group (3.18±1.13) also had higher expression of MyoG mRNA than other groups (1.41±0.65 and 1.03±0.19) at 2 weeks after injection (t=2.72, P=0.04). Transplanted MTMs delayed short-term atrophy of denervated muscles. This approach can be optimized as a novel stand-alone therapy or as a bridge to surgical re-innervation of damaged muscles.

Optimizing stimulation parameters in functional electrical stimulation of denervated muscles: a cross-sectional study.

BACKGROUND: To counteract denervation atrophy long-term electrical stimulation with a high number of muscle contractions has to be applied. This may lead to discomfort of the patient and negative side effects like burns. A functional effective muscle contraction induced by the lowest possible stimulation intensity is desirable. In clinical practice a selective stimulation of denervated muscles with triangular pulses is used. The aim of the study was to evaluate the influence of polarity and pulse duration on the stimulation intensity of triangular pulses in denervated muscles in patients with peripheral nerve lesions. METHODS: Twenty-four patients with denervated extensor digitorum communis muscle and twenty-four patients with denervated tibialis anterior muscle due to peripheral nerve lesions were included. Four different combinations of triangular pulses with various duration and polarity were delivered randomly to the denervated muscles. The threshold intensity to induce a functional effective muscle contraction was noted. One-way within subject ANOVA was used to assess changes in intensity. An alpha level of p less than or equal to 0.05 was the criterion for statistical significance. RESULTS: Patients with a denervated tibialis anterior muscle presented significant lower intensities inducing a functional effective muscle contraction in favor of the stimulation with a duration of 200 ms and a polarity with the cathode proximally applied. No significant differences could be shown between the different stimulation protocols in case of denervated extensor digitorum communis muscle. CONCLUSIONS: We recommend electrical stimulation of the denervated tibialis anterior muscle with triangular current with a duration of 200 ms and a polarity with the cathode proximally applied.

Functional recovery of denervated skeletal muscle with sensory or mixed nerve protection: a pilot study.

Functional recovery is usually poor following peripheral nerve injury when reinnervation is delayed. Early innervation by sensory nerve has been indicated to prevent atrophy of the denervated muscle. It is hypothesized that early protection with sensory axons is adequate to improve functional recovery of skeletal muscle following prolonged denervation of mixed nerve injury. In this study, four groups of rats received surgical denervation of the tibial nerve. The proximal and distal stumps of the tibial nerve were ligated in all animals except for those in the immediate repair group. The experimental groups underwent denervation with nerve protection of peroneal nerve (mixed protection) or sural nerve (sensory protection). The experimental and unprotected groups had a stage II surgery in which the trimmed proximal and distal tibial nerve stumps were sutured together. After 3 months of recovery, electrophysiological, histological and morphometric parameters were assessed. It was detected that the significant muscle atrophy and a good preserved structure of the muscle were observed in the unprotected and protective experimental groups, respectively. Significantly fewer numbers of regenerated myelinated axons were observed in the sensory-protected group. Enhanced recovery in the mixed protection group was indicated by the results of the muscle contraction force tests, regenerated myelinated fiber, and the results of the histological analysis. Our results suggest that early axons protection by mixed nerve may complement sensory axons which are required for promoting functional recovery of the denervated muscle natively innervated by mixed nerve.

Effects of electrical stimulation and stretching on the adaptation of denervated skeletal muscle: implications for physical therapy.

BACKGROUND: This review will describe the main cellular mechanisms involved in the reduction and increase of myoproteins synthesis commonly associated with muscle atrophy and hypertrophy, respectively. OBJECTIVE: We analyzed the effects of electrical stimulation (ES) and stretching exercise on the molecular pathways involved in muscle atrophy and hypertrophy. We also described the main effects and limits of these resources in the skeletal muscle, particularly on the denervated muscle. DISCUSSION: Recently, our studies showed that the ES applied in a similar manner as performed in clinical practice is able to attenuate the increase of genes expression involved in muscle atrophy. However, ES was not effective to prevent the loss of muscle mass caused by denervation. Regarding to stretching exercises, their mechanisms of action on the denervated muscle are not fully understood and studies on this area are scarce. Studies from our laboratory have found that stretching exercise increased the extracellular matrix remodeling and decreased genes expression related to atrophy in denervated muscle. Nevertheless, it was not enough to prevent muscle atrophy after denervation. CONCLUSIONS: In spite of the use of stretching exercise and ES in clinical practice in order to minimize the atrophy of denervated muscle, there is still lack of scientific evidence to justify the effectiveness of these resources to prevent muscle atrophy in denervated muscle.

Effects of electrical stimulation and stretching on the adaptation of denervated skeletal muscle: implications for physical therapy / Efeitos da eletroestimulação e do alongamento muscular sobre a adaptação do músculo desnervado: implicações para a fisioterapia

BACKGROUND: This review will describe the main cellular mechanisms involved in the reduction and increase of myoproteins synthesis commonly associated with muscle atrophy and hypertrophy, respectively. OBJECTIVE: We analyzed the effects of electrical stimulation (ES) and stretching exercise on the molecular pathways involved in muscle atrophy and hypertrophy. We also described the main effects and limits of these resources in the skeletal muscle, particularly on the denervated muscle. DISCUSSION: Recently, our studies showed that the ES applied in a similar manner as performed in clinical practice is able to attenuate the increase of genes expression involved in muscle atrophy. However, ES was not effective to prevent the loss of muscle mass caused by denervation. Regarding to stretching exercises, their mechanisms of action on the denervated muscle are not fully understood and studies on this area are scarce. Studies from our laboratory have found that stretching exercise increased the extracellular matrix remodeling and decreased genes expression related to atrophy in denervated muscle. Nevertheless, it was not enough to prevent muscle atrophy after denervation. CONCLUSIONS: In spite of the use of stretching exercise and ES in clinical practice in order to minimize the atrophy of denervated muscle, there is still lack of scientific evidence to justify the effectiveness of these resources to prevent muscle atrophy in denervated muscle.

CONTEXTUALIZAÇÃO: Esta revisão abordará os principais mecanismos celulares envolvidos na redução e aumento da síntese de mioproteínas comumente associadas às situações de atrofia e hipertrofia muscular, respectivamente. OBJETIVO: Analisaremos os efeitos da estimulação elétrica (EE) e do exercício de alongamento sobre as vias moleculares envolvidas na atrofia e hipertrofia muscular. Serão descritos os principais efeitos e os limites desses recursos no músculo esquelético, particularmente sobre o músculo desnervado. DISCUSSÃO: Recentemente, nossos estudos mostraram que a EE, aplicada de modo semelhante ao realizado na prática clínica, é capaz de amenizar o aumento da expressão de genes envolvidos na atrofia muscular. Entretanto, a EE não foi efetiva para deter a perda de massa muscular decorrente da desnervação. Em relação ao alongamento, seus mecanismos de ação sobre o músculo desnervado não são totalmente conhecidos, e os trabalhos nessa área são escassos. Estudos do nosso laboratório identificaram que o alongamento aumentou o remodelamento da matriz extracelular e diminuiu a expressão de genes relacionados à atrofia no músculo desnervado. Porém, também não foi suficiente para impedir a atrofia muscular após a desnervação. CONCLUSÕES: Apesar do uso da EE e do alongamento muscular na prática clínica, com objetivo de minimizar a atrofia do músculo desnervado, ainda há carência de informações científicas que justifiquem a eficácia desses recursos para prevenir a atrofia no músculo desnervado.

Electrical stimulation prevents apoptosis in denervated skeletal muscle.

The purpose of this study was to investigate the hypothesis that electrical stimulation regulates the levels of gene expression related to apoptosis in denervated muscle and prevents muscle atrophy after denervation.Nineteen rats were used in this study. To denervate soleus muscle, sciatic nerve was resected under aseptic condition. Electrical stimulation with 4 mA rectangular pulses of 0.5 ms duration at 2 Hz lasting for 1 hour was delivered to lower limb including the soleus muscle using two surface electrodes. After the stimulation periods of 4 weeks, the levels of gene expression related to apoptosis were evaluated. Electrical stimulation increased valosin-containing protein (VCP) expression and decreased cleaved caspase-12 expression in denervated muscles. These results indicated that electrical stimulation to denervated muscle suppresses ER-specific apoptosis by enhancing VCP expression. We proposed that electrical stimulation would be a potential treatment for preventing atrophy of denervated skeletal muscles.

Home-based functional electrical stimulation rescues permanently denervated muscles in paraplegic patients with complete lower motor neuron lesion.

BACKGROUND: Spinal cord injury causes muscle wasting and loss of function, which are especially severe after complete and permanent damage to lower motor neurons. In a previous cross-sectional study, long-standing denervated muscles were rescued by home-based functional electrical stimulation (h-bFES) training. OBJECTIVE: To confirm results by a 2-year longitudinal prospective study of 25 patients with complete conus/cauda equina lesions. METHODS: Denervated leg muscles were stimulated by h-bFES using a custom-designed stimulator and large surface electrodes. Muscle mass, force, and structure were determined before and after 2 years of h-bFES using computed tomography, measurements of knee torque during stimulation, and muscle biopsies analyzed by histology and electron microscopy. RESULTS: Twenty of 25 patients completed the 2-year h-bFES program, which resulted in (a) a 35% cross-sectional increase in area of the quadriceps muscle from 28.2 ± 8.1 to 38.1 ± 12.7 cm(2) (P < .001), a 75% increase in mean diameter of muscle fibers from 16.6 ± 14.3 to 29.1 ± 23.3 µm (P < .001), and improvements of the ultrastructural organization of contractile material; and (b) a 1187% increase in force output during electrical stimulation from 0.8 ± 1.3 to 10.3 ± 8.1 N m (P < .001). The recovery of quadriceps force was sufficient to allow 25% of the subjects to perform FES-assisted stand-up exercises. CONCLUSIONS: Home-based FES of denervated muscle is an effective home therapy that results in rescue of muscle mass and tetanic contractility. Important immediate benefits for the patients are the improved cosmetic appearance of lower extremities and the enhanced cushioning effect for seating.

Effect of systemic creatine monohydrate supplementation on denervated muscle during reinnervation: experimental study in the rat.

The purpose of this experimental study was to evaluate possible upgrading effects of systemic creatine monohydrate administration on the reinnervation of denervated muscle. At the same time, the protective effect of the agent on denervated muscle until ultimate reinnervation after nerve repair was quantified. The functional outcome of muscle reinnervation after creatine monohydrate application was compared with a control group. Forty adult Wistar rats weighing 180 to 220 g were used. The right sciatic nerve was dissected, exposed, and cut at the level of the midthigh in all rats. The experimental design consisted of two groups: experimental (animals were fed creatine monohydrate) and control (gavage feeding was provided by saline). Both groups were divided into two subgroups: subgroups A and B for the experimental group, and subgroups C and D for the control group. In subgroups A and C, the nerves were repaired with four 10-0 epineurial stitches. In subgroups B and D, both the proximal and distal ends of the nerves were ligated and no neural anastomosis was performed. In the experimental groups (subgroups A and B), the rats were fed by daily supplementation of oral creatine monohydrate, 300 mg/kg body weight. In the controls (subgroups C and D), oral supplementation was provided by saline. Functional recovery was evaluated using walking track analysis, pinching test, and limb circumference and toe contracture measurements at the end of 6 months, after which the rats were sacrificed and nerve specimens from both ends of the repair sites and the whole gastrocnemius muscle were obtained to document the results of the histomorphometric and histochemical studies, including light microscopic examinations and muscle weight measurements. The mean functional recovery values in subgroups A, B, C, and D were 91 percent, 80 percent, 87 percent, and 59 percent, respectively. Functional recovery improved significantly in the experimental groups (in both the surgically repaired and unrepaired subgroups), compared with the control groups (p<0.05). The pinching test revealed a statistically significant difference in nerve conduction between the experimental and control groups (p<0.05). The limb circumference ratio of the surgically treated side to the untouched side in subgroups A, B, C, and D were noted as 0.95, 0.89, 0.91, and 0.87, respectively, and the difference between the experimental and the control groups was statistically significant (p<0.05). The differences between subgroups A and B, C and D, A and C, and B and D were also significant. The surgically repaired and creatine-supplemented subgroups demonstrated the best results in toe contracture index. The muscle weight measurement results were concordant with the results of the limb circumference ratio. In both surgically repaired subgroups (subgroups A and C), there were qualitatively significant amounts of myelinated fibers in the nerve distal to the anastomotic site; there were no myelinated fibers in the distal stumps of subgroups B and D. Histochemical analyses of the contents of the muscle fiber types also revealed no significant difference. Overall, the results showed the useful effect of oral creatine supplementation on both surgically repaired and unrepaired nerve injuries. The best results were obtained from surgically repaired nerve injuries and also from the systemic creatine-supplemented subgroups. This study confirms that systemic administration of creatine monohydrate has a protective and upgrading effect on the functional properties of denervated muscle, especially in surgically reinnervated subjects.

Acute isolated suprascapular nerve palsy limited to the infraspinatus muscle: a case report.

Suprascapular nerve palsy resulting in isolated weakness of the infraspinatus muscle is subtle at its onset and must be differentiated from cervical radiculopathy or bone and joint diseases of the shoulder, especially in the presence of pain. The literature suggests an association of cumulative trauma with ganglionic cyst formation and entrapment neuropathy of the suprascapular nerve in the spinoglenoid notch. Here we present clinical, electrodiagnostic, and radiologic features in a young patient who presented with a 2-week history of isolated, painless weakness of the right shoulder. His electromyography showed acute denervation of the right infraspinatus muscle. Magnetic resonance imaging revealed a ganglionic cyst in the spinoglenoid fossa and edema in the infraspinatus muscle consistent with denervation. The patient recovered after removal of the cyst.

Role of muscular exercise in amyotrophic lateral sclerosis.

The general, systemic, and specific neuromuscular adaptation to physical exercise and training in healthy individuals is reviewed with application to individuals with neuromuscular disease in general and ALS in particular. A pilot study utilizing patients with ALS suggests the cardiopulmonary response to acute exercise is similar to normal individuals. However, a case study of a training response suggests the success of neuromuscular adaptation will be dependent upon the degree of motor neuron involvement.