Physical therapy protocols to attenuate skeletal muscle atrophy in critically ill patients: narrative review / Protocolos de terapia física para atenuar la atrofia del músculo esquelético en pacientes críticos: revisión narrativa

SUMMARY: To describe the physical therapy protocols used in critically ill patients to attenuate skeletal muscle atrophy. We conducted a search in PubMed and Embase from inception to November 2020. Observational or experimental studies published in English or Spanish that evaluated the effect of physical therapy protocols on the attenuation of skeletal muscle atrophy in critically ill patients through muscle strength or mass measurement were considered eligible. Studies were only included if they reported a detailed description of the dosing of the interventions. Seventeen studies met the eligibility criteria. We included randomised clinical trials (n = 16) and observational studies (n = 1). The total population of the included studies was 872 critically ill patients. The studies aimed to evaluate the reliability, safety or effectiveness of neuromuscular electrical stimulation (n = 10) protocols, early mobilisation (n = 3), ergometer training (n = 2), transfers in tilt table (n = 1), and blood flow restriction (n = 1). Physical therapy protocols are part of the critically ill patient's integral management. Strategies such as passive mobilisation, in-bed and out-of-bed transfers, gait training, ergometer training, and neuromuscular electrical stimulation substantially impact critically ill patients' prognoses and quality of life after hospital discharge.

RESUMEN: Describir los protocolos de terapia física usados en pacientes críticos para atenuar la atrofia muscular esquelética. Realizamos una búsqueda en PubMed y Embase desde el inicio hasta noviembre de 2020. Se consideraron los estudios observacionales o experimentales publicados en inglés o español que evaluaron el efecto de los protocolos de terapia física en la atenuación de la atrofia del músculo esquelético en pacientes críticos a través de la medición de la fuerza o la masa muscular. Los estudios solo se incluyeron si informaron una descripción detallada de la dosificación de las intervenciones. Diecisiete estudios cumplieron los criterios de elegibilidad. Se incluyeron ensayos clínicos aleatorizados (n = 16) y estudios observacionales (n = 1). La población total de los estudios incluidos fue de 872 pacientes en estado crítico. Los estudios tuvieron como objetivo evaluar la confiabilidad, seguridad o efectividad de los protocolos de estimulación eléctrica neuromuscular (n = 10), movilización temprana (n = 3), entrenamiento con ergómetro (n = 2), transferencias en mesa basculante (n = 1) y restricción del flujo sanguíneo (n = 1). Los protocolos de terapia física forman parte del manejo integral del paciente crítico. Es- trategias como la movilización pasiva, los traslados dentro y fuera de la cama, el entrenamiento de la marcha, el entrenamiento con ergómetro y la estimulación eléctrica neuromuscular tienen un impacto sustancial en el pronóstico y la calidad de vida de los pacientes críticos después del alta hospitalaria.

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.

Efeito do exercício aeróbico em modelo experimental de artrite / Effect of aerobic exercise on an experimental model of arthritis

INTRODUÇÃO: A artrite reumatoide é uma doença inflamatória sistêmica autoimune que acomete preferencialmente as articulações, mas também outros tecidos, como o músculo esquelético. A perda de massa muscular determina uma grande repercussão na funcionalidade e qualidade de vida desses pacientes e o exercício físico surge como uma alternativa terapêutica para esse acometimento. OBJETIVO: Avaliar o efeito do exercício físico aeróbico moderado sobre a perda muscular em artrite induzida por colágeno (CIA). MÉTODOS: Esse é um estudo-piloto em que CIA foi induzida em camundongos machos DBA1/J divididos em dois grupos: (i) animais com exercício (EXE, n=5), (ii) animais sem exercício (semEXE, n=4). Foram avaliados o escore clínico, o edema da pata traseira, o peso do animal e a locomoção espontânea periodicamente. Após a morte, a histopatologia da articulação tibiotarsal e a área da miofibra dos músculos gastrocnêmio e tibial anterior foram avaliados. Significância foi considerada se p<0,05.RESULTADOS: Não foi observada diferença significativa entre os grupos nos parâmetros de atividade da doença, peso e locomoção espontânea. Entretanto, a histopatologia da articulação demonstrou redução da erosão cartilaginosa no grupo EXE. Também se observou aumento significativo na área seccional da miofibra do grupo EXE, representando uma diferença média de 24%. CONCLUSÃO: Este é o primeiro estudo com exercício aeróbico moderado em esteira em modelo experimental de artrite. O protocolo de exercício testado não parece impactar no desenvolvimento clínico da doença, mas demonstrou benefício sobre a perda muscular consequente da artrite, reduzindo a atrofia da miofibra.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease that affects primarily the joints, but also other tissues such as skeletal muscle. Muscle wasting significantly impairs the functionality and quality of life of patients with RA and physical exercise is an alternative therapy for this outcome. AIM: To evaluate the effect of moderate aerobic physical exercise on muscle loss caused by collagen-induced arthritis (CIA). METHODS: This is a pilot study in which CIA was induced in DBA/1J mice divided into two groups: (i) animals which exercised (EXE, n=5), (ii) animals which did not exercise (semEXE, n=4). Clinical score, hind paw swelling, weight, and spontaneous locomotion were evaluated periodically. After death, the histopathological score of the ankle and the myofiber area of the gastrocnemius and tibialis anterior muscles were evaluated. Significance was considered when p<0.05. RESULTS: No significant difference was observed between groups regarding clinical parameters of disease activity, animal weight, and spontaneous locomotion. However, joint histopathology demonstrated a decrease in cartilage erosion in the EXE group. There was also significant difference in the myofiber sectional area, with a 24% increase in the EXE group. CONCLUSION: This is the first interventional study with moderate aerobic exercise on a treadmill in an arthritis experimental model. The tested exercise program does not seem to have a clinical impact on the process of arthritis. However, it has a positive effect on muscle wasting caused by arthritis, demonstrated mainly by the reduction of myofiber atrophy.

Metformina minimiza as alterações morfométricas no músculo sóleo de ratos submetidos à imobilização articular / Metformin minimizes the morphometric alterations in the soleus muscle of rats submitted to articular immobilization

A proposta deste trabalho foi avaliar o músculo sóleo (S) de ratos submetidos à imobilização articular por sete dias, associado ou não ao tratamento com metformina (MET, 1,4mg.ml-1) por meio de análises morfométricas. Ratos adultos Wistar (n = 5) foram divididos nos grupos: controle (C), imobilizado em posição neutra do tornozelo (I), tratado com metformina (M), imobilizado tratado com metformina (I + MET). Foram avaliadas a área das fibras, a densidade de área do tecido conjuntivo intramuscular e a massa muscular do S. A análise estatística foi realizada pelo teste de normalidade, ANOVA e de Tukey (p < 0,05). A imobilização reduziu o peso muscular (mg) do S (34 por cento). No grupo M não houve alteração significativa do peso muscular quando comparado com o grupo C. Já no grupo I + MET foi observado aumento do peso muscular em 29,6 por cento quando comparado com o grupo I. O tratamento com metformina não alterou a área da fibra muscular quando comparado com grupo C. Já no grupo I, houve redução de 44 por cento na área da fibra. Com relação ao grupo I + MET, houve aumento de 22 por cento quando comparado com o grupo I. Por outro lado, ao compararmos o grupo C com o grupo I + MET, houve redução de 31 por cento. Ao avaliar a densidade de área do tecido conjuntivo, observou-se que o grupo I apresentou elevação de 216 por cento quando comparado com o grupo C. No grupo I + MET, houve redução de 67 por cento comparado com o grupo I. O tratamento com metformina em músculos submetidos à imobilização minimizou a redução da área das fibras do S, bem como o aumento do tecido conjuntivo. Esses resultados sugerem que a metformina pode favorecer recuperação mais rápida na fase pós-imobilização.

The aim of this study was to evaluate the effect of metformin treatment on the muscle mass, fibers area and connective tissue area density in soleus (S) muscle under articular immobilization. METHODS AND RESULTS: Male Wistar rats (250-300g) were divided in 4 groups (n=5): control, treated with metformin, immobilized and immobilized treated with metformin. Immobilization was performed by acrylic resin orthoses on the left hindlimb keeping the ankle in neutral position during 7 days. The animals were euthanatized and the S muscle was dissected and weighed. Samples of its ventral portion were treated for inclusion in paraffin and stained in Hematoxylin-Eosin (H:E). The results were obtained through analyses of the muscular fiber area (images analyzed - Image Pró-plus 4,0), as well as of intramuscular connective tissue by means of planimetry. The statistical analysis was performed by normality test followed by ANOVA and Tukey (p<0.05). Hindlimb immobilization during 7 days promoted significant reduction (p<0.05) of 35 percent in the muscular mass; 44 percent (p<0.05) in the fiber area and increase of 216 percent (p<0.05) in the intramuscular connective tissue. The metformin in immobilized group promoted significant alterations (p<0.05) in the muscular mass. In addiction, it was observed significant increase (p<0.05) of 29.6 percent in the fibers area and significant reduction (p<0.05) of 67 percent in the intramuscular connective tissue. CONCLUSION: The metformin treatment minimized the reduction of muscle fibers area, as well as the increase of connective tissue in hindlimb immobilized muscle. These results suggest that metformin should be used to increase fast muscle recovery after hindlimb immobilization.

Histomorphometric analysis of the response of rat skeletal muscle to swimming, immobilization and rehabilitation

The objective of the present study was to determine to what extent, if any, swimming training applied before immobilization in a cast interferes with the rehabilitation process in rat muscles. Female Wistar rats, mean weight 260.52 ± 16.26 g, were divided into 4 groups of 6 rats each: control, 6 weeks under baseline conditions; trained, swimming training for 6 weeks; trained-immobilized, swimming training for 6 weeks and then immobilized for 1 week; trained-immobilized-rehabilitated, swimming training for 6 weeks, immobilized for 1 week and then remobilized with swimming for 2 weeks. The animals were then sacrificed and the soleus and tibialis anterior muscles were dissected, frozen in liquid nitrogen and processed histochemically (H&E and mATPase). Data were analyzed statistically by the mixed effects linear model (P < 0.05). Cytoarchitectural changes such as degenerative characteristics in the immobilized group and regenerative characteristics such as centralized nucleus, fiber size variation and cell fragmentation in the groups submitted to swimming were more significant in the soleus muscle. The diameters of the lesser soleus type 1 and type 2A fibers were significantly reduced in the trained-immobilized group compared to the trained group (P < 0.001). In the tibialis anterior, there was an increase in the number of type 2B fibers and a reduction in type 2A fibers when trained-immobilized rats were compared to trained rats (P < 0.001). In trained-immobilized-rehabilitated rats, there was a reduction in type 2B fibers and an increase in type 2A fibers compared to trained-immobilized rats (P < 0.009). We concluded that swimming training did not minimize the deleterious effects of immobilization on the muscles studied and that remobilization did not favor tissue re-adaptation.

Efeitos da remobilização em duas semanas com natação sobre o músculo sóleo de ratos submetidos à imobilização / Effects of remobilization in two weeks of swimming on the soleus muscle of rats submitted to immobilization

Uma importante questão para a reabilitação é como proteger o músculo esquelético dos efeitos da imobilização, pois, o músculo é o mais mutável dentre os tecidos biológicos e responde às demandas normais ou alteradas com adaptações morfológicas e funcionais. O objetivo deste artigo foi verificar o efeito de duas diferentes intensidades de carga de natação sobre a morfologia do músculo sóleo, e se são eficazes para reverter o processo de atrofia causado pela imobilização durante o período de 15 dias. Foram utilizados 10 ratos, com idade de 10±2 semanas, divididos em 2 grupos: G1 (imobilização/natação sem peso) e G2 (imobilização/natação com sobrecarga de 10 por cento do peso corporal). Dentro das variáveis analisadas ao comparar o membro esquerdo (submetido à imobilização) com o direito (não submetido) foram observados: para peso muscular em G1=-20,55 por cento (p=0,0344) e G2= -17,02 por cento (p=0,0053); comprimento muscular em G1= -10,66 por cento (p=0,0011) e G2= -6,55 por cento (p=0,1016); estimativa de sarcômeros em série no músculo para G1= -14,18 por cento (p=0,0101) e G2= -10,99 por cento (p=0,0043); e para comprimento de sarcômeros em G1= 3,51 por cento (p=0,3989) e G2= 5,28 por cento (p=0,1771). Conclui-se que duas semanas de remobilização através da natação, com diferentes tipos de sobrecarga não foram suficientes para reverter totalmente o processo de atrofia causado pela imobilização.

An important issue in rehabilitation is how to protect the skeletal muscle from immobilization effects, since it is the most changeable tissue amongst the biological tissues and responds to normal or modified demands with morphological and functional adaptations. The objective of this paper was to check the effect of two different swimming load intensities on the morphological properties of the soleus muscle, and if the different degrees of swimming are effective to reverse the process of atrophy caused by immobilization during 15 days. Ten rats, 10±2 weeks were used and divided in 2 groups:G1(immobilization/swimming without overload) and G2 (immobilization/swimming with 10 percent overload). Within the variable analyzed, when the left limb (submitted to immobilization) was compared with the right limb (not submitted) it was observed: for muscle weight G1=-20.55 percent (p=0.0344) and G2= -17.02 percent (p=0.0053); for muscle length G1= -10.66 percent (p=0.0011) and G2= -6.55 percent (p=0.1016); for serial sarcomere estimate G1= -14.18 percent (p=0.0101) and G2= -10.99 percent (p=0.0043); and sarcomere length G1= 3.51 percent (p=0.3989) and G2= 5.28 percent (p=0.1771). It has been concluded that two weeks of remobilization through swimming, with different degrees of overload, were not sufficient to reverse the atrophy process caused by immobilization.

One-minute bouts of passive stretching after immobilization increase sarcomerogenesis in rat soleus muscle

Although the effect of stretching on skeletal muscle has been investigated, the mechanical influence of short bouts of passive stretch, commonly used in rehabilitation therapy to recover skeletal muscle length after immobilization, has not been studied in detail. The hypothesis of this study was that one-minute bouts of muscle stretching applied after immobilization would induce sarcomerogenesis in muscle fibers. To assess this hypothesis, sessions of passive stretching (10 stretches of 1 min each with 30 s rests between stretches) were applied daily or three times a week to the left soleus muscle after immobilization in the shortened position. Eighteen rats were immobilized for four weeks and divided into three groups: 1) after immobilization, the rats remained free for three weeks, 2) the soleus muscle was stretched daily for three weeks, and 3) the soleus muscle was stretched three times a week for three weeks. A control group was run in parallel. The crosssectional area of the soleus muscle fibers and the serial number and length of sarcomeres were measured. Both of the stretch protocols increased the serial number of sarcomeres, but not the cross-sectional area of the muscle fibers. In conclusion, short bouts of passive stretching alter the muscle fiber tropism and induce serial sarcomerogenesis after immobilization.