Preserve Muscle Function Research Articles

A Review of Minimally Invasive Strabismus Surgery (MISS): Is This the Way Forward?

Minimally invasive surgery is rapidly becoming the norm in medicine, as it often leads to better outcomes and earlier rehabilitation. This article reviews the principles and different techniques employed to perform minimally invasive strabismus surgery (MISS). In these techniques, strabismus surgery is performed through keyhole openings, thus reducing the risk of postoperative corneal complications, minimizing postoperative discomfort, and better preserving muscle function. MISS can be used to perform all types of strabismus surgery, namely rectus muscle recessions, resections, plications, reoperations, retroequatorial myopexy, transpositions, oblique muscle recessions, or plications even in the presence of limited motility. Of note, ocular alignment outcomes with MISS versus more traditional techniques have not been compared in randomized trials. Consequently, more controlled evidence is still needed to better delineate the future role and value of MISS in clinical management.

Effects of Neuromuscular Electrical Stimulation Training on Endurance Performance.

Various electrical stimulation modalities are used as adjuvants to conventional training and rehabilitation programs to increase bodily function or to reduce symptoms, such as pain. One of these modalities, neuromuscular electrical stimulation (NMES), commonly refers to the transcutaneous application of electrical currents to a target muscle group with the objective to depolarize motor neurons and consequently elicit skeletal muscle contractions of substantial intensity (usually ranging from 10 to 60% of the maximal voluntary contraction). Because NMES can generate considerable muscle tension, it is frequently used as a strength training technique for healthy adults and athletes, but also as a rehabilitation tool to increase or preserve muscle function and mass in individuals with muscle weakness or patients who cannot perform voluntary contractions [e.g., patients suffering from chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), or critical illness; for reviews, see Roig and Reid, 2009; Sillen et al., 2009; Sbruzzi et al., 2010; Maddocks et al., 2011; Maffiuletti et al., 2011; Smart et al., 2013; Burke et al., 2016]. Under certain conditions, NMES training may also improve muscle oxidative capacity and result in a fast-to-slow muscle fiber type transition (Perez et al., 2002; Gondin et al., 2011a), which could potentially enhance endurance performance. However, the relevance of such adaptations in skeletal muscle tissue for the translation to functional performance that is particularly important for sport and daily activities is not always self-evident, mainly because of the heterogeneity in study populations, NMES parameters, and outcome measures. Unfortunately, the bodies of literature that either focus on mechanistic (i.e., muscle endurance) or clinical (i.e., functional endurance) outcomes are often too disconnected. In this opinion paper, we aim to bring these bodies of literature together and discuss the impact of high- vs. low-frequency NMES training on muscle vs. functional endurance in healthy vs. clinical populations. As such, we focus on human studies that chronically applied NMES for at least 3 weeks in healthy persons and patients, and distinguish between the effectiveness of non-tetanic low-frequency NMES (that is usually administered continuously at frequencies close to 10 Hz) and tetanic high-frequency NMES (that is usually administered intermittently at frequencies close to 50 Hz) on muscle endurance and functional endurance. For clarity purposes, we refer to muscle endurance as the exercise-induced decline in voluntary or electrically-evoked force (Duchateau and Hainaut, 1988; Gondin et al., 2006) or the endurance time of a sustained single-joint contraction (Gondin et al., 2006). In contrast, we refer to functional endurance as the maximal oxygen consumption or workload (Perez et al., 2002; Porcelli et al., 2012), the distance covered in a given time (e.g., 6-minute walk test) or the endurance time (Kim et al., 1995) for whole-body exercises such as walking and cycling. In the last section, we will provide some recommendations for better clinical use of NMES, and suggest potential directions for future research.

The Concepts of Propeller, Perforator, Keystone, and Other Local Flaps and Their Role in the Evolution of Reconstruction.

After studying this article, the participant should be able to: 1. Understand the history and physiology of perforator flaps. 2. Understand the concept of "free-style" perforator flaps and principles in design and harvest. 3. Understand the uses of perforator flaps in reconstruction and applications in new settings. 4. Understand new principles in single and multiple perforator flap harvest and adjunct techniques that can be used in perforator flaps. 5. Highlight pertinent anatomy and techniques for selected perforator flaps described. Extended knowledge of vascular anatomy has propagated the development of perforator flaps, which preserve muscle function and reduce morbidity. This has been achieved through the exemplary works of Manchot, Salmon, Milton, Taylor, and many others. With over 350 clinically relevant perforators in the body, this has created new flap options and a sense of creative freedom for reconstruction tailored toward a specific defect, without constraints of specific landmarks and using a "free-style" approach. Dominant perforators may be found in zones of high perforator density or "hot spots," which can help to conceptualize local flap options and aid flap design. This article aims to outline the history, physiology, and principles of flap design and harvest, and highlight traditional and evolving concepts and modifications of contemporary and traditional flaps that are changing reconstructive practice. This is a broad overview focusing on clinical applications, highlighting key concepts in a selection of new or evolving flaps being used in clinical practice and providing source references to acquire detailed flap descriptions.

Skeletal muscle fiber size and fiber type distribution in human cancer: Effects of weight loss and relationship to physical function

Cancer patients frequently experience weight loss, with negative consequences for functionality and prognosis. The extent to which muscle atrophy contributes to weight loss, however, is not clear, as few studies have directly measured muscle fiber morphology in cancer patients. Whole body and regional tissue composition were measured, along with the cross-sectional area (CSA) and fiber type of mechanically-isolated, single muscle fibers, in 19 cancer patients (8 with a history of weight loss, 11 weight-stable) and 15 non-diseased controls. Whole body fat mass was reduced in cancer patients with a history of weight loss, but no differences in whole body or leg fat-free mass were apparent. In contrast, reductions (∼20%) in single muscle fiber CSA were found in both slow-twitch, myosin heavy chain (MHC) I and fast-twitch, MHC IIA fibers in both weight-stable patients and those with a history of weight loss. Fiber type distribution showed a shift towards a fast-twitch phenotype compared to controls, which may preserve muscle function in cancer patients despite atrophy, as positive relationships were found between the fractions of hybrid MHC IIAX and I/IIA fibers and 6-min walk performance. Our results suggest that, although not apparent from whole body or regional measurements, cancer is associated with reduced skeletal muscle fiber size independent of weight loss history and a shift towards fast-twitch fibers, phenotypes that resemble adaptations to muscle disuse.

Fourteen days of bed rest induces a decline in satellite cell content and robust atrophy of skeletal muscle fibers in middle-aged adults.

Bed rest, a ground-based spaceflight analog, induces robust atrophy of skeletal muscle, an effect that is exacerbated with increasing age. We examined the effect of 14 days of bed rest on skeletal muscle satellite cell content and fiber type atrophy in middle-aged adults, an understudied age demographic with few overt signs of muscle aging that is representative of astronauts who perform long-duration spaceflight. Muscle biopsies were obtained from the vastus lateralis of healthy middle-aged adults [n= 7 (4 male, 3 female); age: 51 ± 1 yr] before (Pre-BR) and after (Post-BR) 14 days of bed rest. Immunohistochemical analyses were used to quantify myosin heavy chain (MyHC) isoform expression, cross-sectional area (CSA), satellite cell and myonuclear content, and capillary density. Peak oxygen consumption, knee extensor strength, and body composition were also measured Pre-BR and Post-BR. Post-BR MyHC type 2a fiber percentage was reduced, and mean CSA decreased in all fiber types (-24 ± 5%;P< 0.05). Satellite cell content was also reduced Post-BR (-39 ± 9%;P< 0.05), and the change in satellite cell content was significantly correlated with the change in mean fiber CSA (r(2)= 0.60;P< 0.05). A decline in capillary density was observed Post-BR (-23 ± 6%;P< 0.05), and Post-BR capillary content was significantly associated with Post-BR peak aerobic capacity (r(2)= 0.59;P< 0.05). A subtle decline in myonuclear content occurred during bed rest (-5 ± 1%;P< 0.05). The rapid maladaptation of skeletal muscle to 14 days of mechanical unloading in middle-aged adults emphasizes the need for robust countermeasures to preserve muscle function in astronauts.

Innervation and neuromuscular control in ageing skeletal muscle

Changes in the neuromuscular system affecting the ageing motor unit manifest structurally as a reduction in motor unit number secondary to motor neuron loss; fibre type grouping due to repeating cycles of denervation-reinnervation; and instability of the neuromuscular junction that may be due to either or both of a gradual perturbation in postsynaptic signalling mechanisms necessary for maintenance of the endplate acetylcholine receptor clusters or a sudden process involving motor neuron death or traumatic injury to the muscle fibre. Functionally, these changes manifest as a reduction in strength and coordination that precedes a loss in muscle mass and contributes to impairments in fatigue. Regular muscle activation in postural muscles or through habitual physical activity can attenuate some of these structural and functional changes up to a point along the ageing continuum. On the other hand, regular muscle activation in advanced age (>75 years) loses its efficacy, and at least in rodents may exacerbate age-related motor neuron death. Transgenic mouse studies aimed at identifying potential mechanisms of motor unit disruptions in ageing muscle are not conclusive due to many different mechanisms converging on similar motor unit alterations, many of which phenocopy ageing muscle. Longitudinal studies of ageing models and humans will help clarify the cause and effect relationships and thus, identify relevant therapeutic targets to better preserve muscle function across the lifespan.

Redox signaling in skeletal muscle: role of aging and exercise.

Skeletal muscle contraction is associated with the production of ROS due to altered O2 distribution and flux in the cell. Despite a highly efficient antioxidant defense, a small surplus of ROS, such as hydrogen peroxide and nitric oxide, may serve as signaling molecules to stimulate cellular adaptation to reach new homeostasis largely due to the activation of redox-sensitive signaling pathways. Recent research has highlighted the important role of NF-κB, MAPK, and peroxisome proliferator-activated receptor-γ coactivator-1α, along with other newly discovered signaling pathways, in some of the most vital biological functions, such as mitochondrial biogenesis, antioxidant defense, inflammation, protein turnover, apoptosis, and autophagy. There is evidence that the inability of the cell to maintain proper redox signaling underlies some basic mechanisms of biological aging, during which inflammatory and catabolic pathways eventually predominate. Physical exercise has been shown to activate various redox signaling pathways that control the adaptation and remodeling process. Although this stimulatory effect of exercise declines with aging, it is not completed abolished. Thus, aged people can still benefit from regular physical activity in the appropriate forms and at proper intensity to preserve muscle function.

Preserving muscle health and wellbeing for long-term cancer survivors.

The anti-tumour activities of anthracycline antibiotics like doxorubicin (DOX) were first established in the 1960s. Since then they rank among the most effective anti-tumour therapeutics. An example of their impact is seen in the shift of 5 year survival rates for childhood cancer, from 30% to 80% since the 1960s (Stěrba et al. 2013). Topoisomerase IIα is a main target of anthracycline anti-tumour activity. Anthracyclines prevent topoisomerase-mediated relaxation of supercoiled DNA and subsequent DNA replication. Along with effectiveness as a cancer chemotherapy come dangerous side effects that include cardiovascular and respiratory muscle toxicity (Gilliam & St Clair, 2011, Stěrba et al. 2013). Toxicity can develop shortly after treatment or decades later, as is seen among childhood cancer survivors (Stěrba et al. 2013). The mechanism of anthracycline-induced muscle toxicity is still in question. Contributing factors include oxidative stress, calcium dysregulation, and calpain degradation of titin (Stěrba et al. 2013). Muscle mitochondria appear to be at the centre of the problem. First, anthracyclines, known for their ability to produce free radicals, concentrate in mitochondria via an affinity for cardiolipin (Stěrba et al. 2013). Cardiolipin is an inner mitochondrial membrane phospholipid associated with cytochrome c (Kroemer et al. 2007). Second, mitochondria subjected to oxidative stress affect cellular calcium dynamics (Kroemer et al. 2007). Thus, concentrated anthracycline-mediated free radical production in mitochondria might alter cellular calcium dynamics, and subsequent calcium-regulated calpain activity. In this issue of The Journal of Physiology, Min et al. (2015) linked DOX-induced mitochondrial oxidative stress to calpain activation and cardiac/skeletal muscle dysfunction. They demonstrated that pretreatment with the mitochondrial specific antioxidant SS-31, or the calpain inhibitor SJA 6017, protected rats from DOX-induced muscle toxicity. SS-31 preserved mitochondrial respiratory function, reduced cellular oxidative stress, and prevented calpain activation. Both SS-31 and SJA preserved diastolic and systolic cardiac function and diaphragm contractile function, and reduced skeletal muscle atrophy. The fact that SS-31 prevented calpain activation in heart and skeletal muscle supports the idea that DOX alters mitochondrial redox balance to stimulate calpain (Fig.​(Fig.1).1). Interestingly, both DOX and SS-31 target mitochondria through interaction with cardiolipin (Szeto, 2014). The key to SS-31 efficacy may lie in this interaction. As mentioned above, cardiolipin associates with a major fraction of mitochondrial cytochrome c and cardiolipin oxidation leads to cytochrome c release (Orrenius & Zhivotovsky, 2005). Thus, disruption of cardiolipin–cytochrome c complexes either by physical interaction with, or oxidation by, DOX could lead to cytochrome c release. The resulting cytosolic cytochrome c would promote Ca2+ release from the endoplasmic reticulum (Orrenius & Zhivotovsky, 2005) to activate calpain (Kroemer et al. 2007). SS-31 disruption of a DOX-cardiolipin interaction or cardiolipin oxidation could prevent the initiation of this cytotoxic cascade. Figure 1 Mitochondria and muscle toxicity In summary, these results provide further evidence that mitochondria are central to anthracycline-induced muscle toxicity. They also define a pathway initiated by DOX that triggers mitochondrial changes which stimulate calpain to promote muscle dysfunction and atrophy. Finally they demonstrate the potential for therapies targeted to mitochondria or calpain that would preserve muscle function and prevent dangerous long-term side effects of cancer chemotherapy.

The influence of estradiol on muscle damage and leg strength after intense eccentric exercise.

To examine the influence of estradiol on muscle damage and leg strength after intense eccentric exercise. Eight men (MEN), eight normally menstruating women (WomenNM), and eight women using oral contraceptives (WomenOC) participated in this study. Subjects performed 240 maximal-effort bilateral eccentric contractions of the quadriceps muscle groups designed to elicit exercise-induced muscle damage (EiMD). Serum creatine kinase (CK), myoglobin (Mb), and fatty acid-binding protein (FABP) concentrations were measured before (pre-) EiMD, as well as 0, 6, 24, and 48 h post-EiMD. Peak isometric quadriceps torque (i.e., leg strength) was measured pre-EiMD, as well as 24 and 48 h post-EiMD. The increases in CK, Mb, and FABP concentrations from pre- to post-EiMD were greater in MEN (10-fold, 15-fold, and fourfold, respectively) and WomenOC (sevenfold, 11-fold, and ninefold) compared with WomenNM (five-, six-, and threefold; p < 0.05). The decline in leg strength was about 10 % pre- to 24 h post-EiMD in all groups and decreased a further 10-15 % by 48 h post-EiMD in the MEN and WomenOC only. Our findings suggest an important role of estradiol in blunting the muscle damage response to intense eccentric exercise and preserving muscle function after EiMD.

Endogenous mesenchymal stromal cells in bone marrow are required to preserve muscle function in mdx mice.

The physiological role of "endogenous" bone marrow (BM) mesenchymal stromal cells (MSCs) in tissue regeneration is poorly understood. Here, we show the significant contribution of unique endogenous BM-MSC populations to muscle regeneration in Duchenne muscular dystrophy (DMD) mice (mdx). Transplantation of BM cells (BMCs) from 10-week-old mdx into 3-4-week-old mdx mice increased inflammation and fibrosis and reduced muscle function compared with mdx mice that received BMCs from 10-week-old wild-type mice, suggesting that the alteration of BMC populations in mdx mice affects the progression of muscle pathology. Two distinct MSC populations in BM, that is, hematopoietic lineage (Lin)(-) /ckit(-) /CD106(+) /CD44(+) and Lin(-) /ckit(-) /CD106(+) /CD44(-) cells, were significantly reduced in 10-week-old mdx mice in disease progression. The results of a whole-transcriptome analysis indicated that these two MSC populations have distinct gene expression profiles, indicating that the Lin(-) /ckit(-) /CD106(+) /CD44(+) and Lin(-) /ckit(-) /CD106(+) /CD44(-) MSC populations are proliferative- and dormant-state populations in BM, respectively. BM-derived Lin(-) /CD106(+) /CD44(+) MSCs abundantly migrated to damaged muscles and highly expressed tumor necrosis factor-alpha-stimulated gene/protein-6 (TSG-6), an anti-inflammatory protein, in damaged muscles. We also demonstrated that TSG-6 stimulated myoblast proliferation. The injection of Lin(-) /ckit(-) /CD106(+) /CD44(+) MSCs into the muscle of mdx mice successfully ameliorated muscle dysfunction by decreasing inflammation and enhancing muscle regeneration through TSG-6-mediated activities. Thus, we propose a novel function of the unique endogenous BM-MSC population, which countered muscle pathology progression in a DMD model.

Hyperglycemia predicts persistently lower muscle strength with aging.

OBJECTIVEPersons with diabetes have accelerated muscle loss compared with their counterparts. The relationship of hyperglycemia per se to declines in muscle function has not been explored yet has implications for developing appropriate intervention strategies to prevent muscle loss.RESEARCH DESIGN AND METHODSWe examined 984 participants aged 25–96 years in the Baltimore Longitudinal Study of Aging (2003–2011) with HbA1c, knee extensor strength (isokinetic dynamometer), and lean body mass (DEXA) measured at baseline. Participants had repeated measurements up to 7.5 years later. Muscle quality was defined as knee extensor strength/leg lean mass. Participants were categorized by HbA1c quartile (<5.5, 5.5–5.79, 5.8–6.09, and ≥6.1% or <37, 37–40, 40–43, and ≥43 mmol/mol). Mixed-effects regression models were used to examine the regression of muscle outcomes on HbA1c.RESULTSMuscle strength and quality were significantly lower across HbA1c quartiles (both P < 0.001), without differences in muscle mass at baseline. Comparing highest versus lowest HbA1c quartiles and adjusting for age, race, sex, weight, and height, strength was significantly lower (−4.70 ± 2.30 N · m; P value trend = 0.02) and results were unchanged after adjustment for physical activity (P value trend = 0.045) but of borderline significance after additional adjustment for peripheral neuropathy (P value trend = 0.05). Adjusting for demographics, muscle quality was significantly lower (−0.32 ± 0.15 N · m/kg; P value trend = 0.02) in the highest versus lowest HbA1c quartiles, but differences were attenuated after adjusting for weight and height (−0.25 ± 0.15 N · m/kg; P value trend = 0.07). Muscle mass measures were similar across HbA1c quartiles.CONCLUSIONSHyperglycemia is associated with persistently lower muscle strength with aging, but this effect may be mediated, at least in part, by peripheral neuropathy. Future studies should explore if better glycemic control can preserve muscle function in diabetes.

Once-weekly muscle endurance and strength training prevents deterioration of muscle oxidative function and attenuates the degree of strength decline during 3-week forearm immobilization.

Muscle unloading causes muscle function deterioration, but the extent to which training frequency or volume can be reduced while preserving muscle function during muscle unloading is unknown. We examined the effects of low-volume muscle endurance and strength training on forearm muscle oxidative capacity, endurance, and strength during a 3-week immobilization. Twenty-seven, healthy, male volunteers were divided into four groups: immobilization only (IMM); immobilization with endurance and strength training, once-weekly (IMM + EST1) or twice-weekly (IMM + EST2); and control, without immobilization or training (CNT). Endurance training involved dynamic handgrip exercise, at 30% of maximal voluntary contraction (MVC), until exhaustion (~60 s). Strength training involved intermittent isometric handgrip exercise at 70% MVC (40 s). Muscle oxidative capacity was evaluated after exercise using the phosphocreatine recovery time constant using (31)phosphorus magnetic resonance spectroscopy. Endurance performance was evaluated according to the total work during dynamic handgrip exercise at 30% MVC at 1 Hz until exhaustion. Muscle oxidative capacity and total work deterioration was restricted to the IMM (P < 0.05) group. MVC decreased in the IMM and IMM + EST1 (P < 0.05) groups. However, the MVC amplitude decrease in the IMM + EST1 group was smaller than that in the IMM (P < 0.05) group. MVC remained unchanged in the other groups. During the 3-week immobilization, twice-weekly low-volume muscle endurance and strength training prevented deterioration in muscle strength, oxidative capacity, and endurance performance. Moreover, once-weekly muscle endurance and strength training prevented the deterioration of muscle oxidative capacity and endurance performance, and attenuated the degree of muscle strength decline.

G.P.84: Muscle physiology properties of mouse models for Duchenne muscular dystrophy

Duchenne muscular dystrophy is a severe muscle wasting disorder, caused by the loss of dystrophin. Since dystrophin is needed to maintain fiber stability during contractions, its absence results in fragile fibers, which are prone to exercise induced damage. In contrast to DMD patients, the mdx mouse model is less severely affected due, at least in part, to overexpression of the dystrophin homologue utrophin. To determine the role of utrophin in maintaining muscle strength and integrity, we performed in vivo force measurements in the tibialis anterior (TA) of 8week old dystrophic mice expressing utrophin on two ( mdx ), one ( mdx-utrn+/ −) or zero alleles ( mdx-utrn − / −). The specific force was significantly lower in all dystrophic compared to wild type mice, and mdx-utrn − / − mice performed significantly worse than mdx and mdx-utrn+/ − mice. Although mdx mice produced lower forces than wild type mice, the force frequency relationship curves followed a similar pattern. A substantial increase in force was observed upon stimulation with higher frequencies (>80Hz) in mdx mice. Contrastingly, lower frequencies ( mdx-utrn+/ − mice, while their maximum specific force was comparable to mdx mice. This suggested that the proportions of slow and fast fibers differed between the dystrophic models. Histologically, we confirmed a shift towards slow fibers in the TAs of mdx-utrn+/ − and −/− mice, whereas in mdx and wild type mice predominantly fast fibers were found. Eccentric (lengthening) contractions provoked a large force drop in mdx mice, while wild type mice were resistant. Interestingly, slow muscle fibers of mdx-utrn+/ − mice enabled better maintenance of force during eccentric contractions than seen in mdx mice. Mdx-utrn − / − mice did not show a drop in force as they were already very weak at protocol initiation. These results suggest that loss of utrophin provokes a shift towards slow fibers which partly preserves muscle function in heterozygotes.

Heat shock proteins protect skeletal muscle against frostbite injury (1102.43)

Backgound: Frostbite injury results in serious skeletal muscle damage. Potentially the inflammatory response due to frostbite causes local muscle degeneration. Previous studies have shown that the heat shock proteins (hsp) are able to protect against oxidative stress and inflammation.Results: In the present study we examined the effects of the heat shock protein inducer, 17‐Dimethylaminoethylamino‐17‐demethoxygeldanamycin (17‐DMAG) which was administered within 45 minutes following frostbite injury. Our results show that rat hind‐limb muscles injected with 17‐DMAG following frostbite injury exhibit less inflammatory cell infiltration as compared to control rat hind‐limb muscles. In agreement with this observation, we found that the increased heat shock protein expression results in a decrease in inflammatory cytokine expression. We also found that administration of 17‐DMAG after frostbite injury is able to preserve muscle function. Our results therefore suggest that 17‐DMAG protects skeletal muscle if administered shortly after frostbite injury.Conclusion: We conclude that compounds such as 17‐DMAG that induce heat shock proteins are able to preserve skeletal muscle function and structure if injected within 45 minutes after frostbite injury. Our studies provide the basis for the development of a potential therapeutic strategy to treat injury caused by frostbite.Grant Funding Source: This research was supported by an award from the USAMRMC.

The Lower Trapezius Musculocutaneous Flap for Head and Neck Reconstruction

Microsurgical free flap has gained the popularity over pedicle flap nowadays in the reconstruction of head and neck. However, pedicled flaps remain a promising alternative and have a remarkable position in selected patients. This review study aimed to determine the reliability and versatility of the lower trapezius musculocutaneous flap for reconstructing complex defects in the head and neck. Between 1993 and 2012, 22 male and 10 female patients underwent a total of 32 lower trapezius flap reconstructions for complex defects that included neoplasm extirpation (n = 21), radionecrosis (n = 6), dehisced laminectomy (n = 2), pressure sore (n = 2), and necrotizing fasciitis (n = 1). The most common site of defect was the perioral region, followed by the neck, posterior skull, back, temporal region, shoulder, and the upper arm. Flap design was based on the defect size and location, as well as the ability to close the donor site primarily and to preserve muscle function. Outcome has been evaluated by the hospital course, postoperative morbidity, mortality, resultant cosmetics, and function at donor and recipient sites. Stable wound coverage with total flap survival was achieved in 30 (93.75%) patients, 2 patients had partial flap necrosis which required flap reinsertion and skin graft coverage. All donor sites were closed primarily. Seroma developed in 2 (6.25%) patients, which were solved by needle aspiration. All muscle function was preserved. Eight patients died of their primary disease. For selected patients who have advanced stage cancer, surgical sequelae after free flap surgery, unable to tolerate microsurgery, or special defect location, pedicled lower trapezius musculocutaneous flap provides efficient and effective reconstruction for complex defects especially in the head and neck.

Nitric oxide and muscle repair: Multiple actions converging on therapeutic efficacy

Muscular dystrophies comprise an heterogeneous group of diseases characterised by primary wasting of skeletal muscle, in the most severe forms leading to progressive paralysis and death. Current therapies for these conditions are extremely limited and based on corticosteroids that bear significant side effects. Several studies have proposed possible alternative strategies, ranging from cell and gene therapy to more classical pharmacological approaches. Nitric oxide is a gaseous messenger involved in many mechanisms responsible for preserving muscle function and stimulating muscle repair. We herein review the most recent pre-clinical and clinical findings that open new prospective for the development of nitric oxide as a therapeutic tool for muscular dystrophies.

Alpha 7 integrin preserves the function of the extensor digitorum longus muscle in dystrophin-null mice

The dystrophin-associated glycoprotein complex (DGC) and the α7β1-integrin complex are two independent protein complexes that link the extracellular matrix with the cytoskeleton in muscle cells. These associations stabilize the sarcolemma during force transmission. Loss of either one of these complexes leads to muscular dystrophy. Dystrophin is a major component of the DGC. Its absence results in Duchenne muscular dystrophy (DMD). Because α7-integrin overexpression has been shown to ameliorate muscle histopathology in mouse models of DMD, we hypothesize that the α7β1-integrin complex can help preserve muscle function. To test this hypothesis, we evaluated muscle force, elasticity, and the viscous property of the extensor digitorum longus muscle in 19-day-old normal BL6, dystrophin-null mdx4cv, α7-integrin-null, and dystrophin/α7-integrin double knockout mice. While nominal changes were found in single knockout mice, contractility and passive properties were significantly compromised in α7-integrin double knockout mice. Our results suggest that DGC and α7β1-integrin complexes may compensate each other to maintain normal skeletal muscle function. α7β1-Integrin upregulation may hold promise to treat not only histological, but also physiological, defects in DMD.

P.11.15 Recombinant human insulin-like growth factor-I (IGF-I) therapy in Duchenne Muscular Dystrophy (DMD): A 6-month prospective randomized controlled trial

Glucocorticoids (GC) delay motor decline in DMD, but cause significant endocrine adverse effects. IGF-I offers potential as a therapeutic agent; it may improve or preserve muscle function and counter GC effects of growth failure and insulin resistance. To determine if IGF-I therapy (1) improves or preserves muscle function and (2) improves linear growth in DMD. Prospective randomized controlled trial of IGF-I therapy in pre-pubertal, ambulatory, GC-treated DMD boys (n = 17) compared to controls (GC alone, n = 21). IGF-I 160 mcg/kg was given daily subcutaneously for 6 months. Primary motor outcome was 6-min walk distance (6MWD), and endocrine outcomes were height velocity and change in height SD score (ΔHtSDS). Other outcomes included changes in timed motor tests, cardiopulmonary function, insulin sensitivity and safety. The difference of 6MWD between control and IGF-I groups at 6 months was 8.5 ± 7.0 m (mean ± SEM, p > 0.5). There were no significant differences between groups for changes in cardiopulmonary and other motor functional outcomes. Height velocity in IGF-I treated subjects was double that of controls at 6 months (6.5 ± 0.4 vs. 3.3 ± 0.3 cm/yr, p In this first study of IGF-I therapy in DMD boys, 6 months of daily IGF-I significantly increased height velocity and HtSDS compared to controls, but there was no difference in motor functional outcomes.

P.20.6 Muscle physiology properties of mouse models for Duchenne muscular dystrophy

Duchenne muscular dystrophy is a severe muscle wasting disorder, caused by the loss of dystrophin. Since dystrophin is needed to maintain fiber stability during contractions, its absence results in fragile fibers, which are prone to exercise induced damage. In contrast to DMD patients, the mdx mouse model is less severely affected due, at least in part, to overexpression of the dystrophin homologue utrophin. To determine the role of utrophin in maintaining muscle strength and integrity, we performed in vivo force measurements in the tibialis anterior (TA) of 8week old dystrophic mice expressing utrophin on two (mdx), one (mdx-utrn+/−) or zero alleles (mdx-utrn−/−). The specific force was significantly lower in all dystrophic compared to wild type mice, and mdx-utrn−/− mice performed significantly worse than mdx and mdx-utrn+/− mice. Although mdx mice produced lower forces than wild type mice, the force frequency relationship curves followed a similar pattern. A substantial increase in force was observed upon stimulation with higher frequencies (>80Hz) in mdx mice. Contrastingly, lower frequencies (<80Hz) resulted in higher forces in mdx-utrn+/− mice, while their maximum specific force was comparable to mdx mice. This suggested that the proportions of slow and fast fibers differed between the dystrophic models. Histologically, we confirmed a shift towards slow fibers in the TAs of mdx-utrn+/− and −/− mice, whereas in mdx and wild type mice predominantly fast fibers were found. Eccentric (lengthening) contractions provoked a large force drop in mdx mice, while wild type mice were resistant. Interestingly, slow muscle fibers of mdx-utrn+/− mice enabled better maintenance of force during eccentric contractions than seen in mdx mice. Mdx-utrn−/− mice did not show a drop in force as they were already very weak at protocol initiation. These results suggest that loss of utrophin provokes a shift towards slow fibers which partly preserves muscle function in heterozygotes.

Effect of citrulline on muscle functions during moderate dietary restriction in healthy adult rats

Low calorie diets are designed to reduce body weight and fat mass, but they also lead to a detrimental loss of lean body mass, which is an important problem for overweight people trying to lose weight. In this context, a specific dietary intervention that preserves muscle mass in people following a slimming regime would be of great benefit. Leucine (LEU) and Citrulline (CIT) are known to stimulate muscle protein synthesis (MPS) in post-prandial and post-absorptive state, respectively. This makes them interesting bioactive components to test in the context of dietary restriction. We tested the concept of combining LEU and CIT in adult female rats. We postulated that the sequential administration of LEU (mixed in chow) and CIT (given in drinking water before a rest period) could be beneficial for preservation of muscle function during food restriction. Sixty female rats (22 weeks old) were randomized into six groups: one group fed ad libitum with a standard diet (C) and five food-restricted groups (60 % of spontaneous intake for 2 weeks) receiving a standard diet (R group), a CIT-supplemented diet (0.2 or 1 g/kg/day, CIT0.2 group and CIT1 group, respectively), a LEU-supplemented diet (1.0 g/kg/day) or a CIT + LEU-supplemented diet (CIT + LEU 1.0 g/kg/day each). At the end of the experiment, body composition, muscle contractile properties and muscle protein synthesis (MPS) rate were studied in the tibialis anterior muscle. Dietary restriction tended to decrease MPS (R: 2.5 ± 0.2 vs. C: 3.4 ± 0.4 %/day, p = 0.06) and decrease muscle strength (R: 3,045 ± 663 vs. C: 5,650 ± 661 A.U., p = 0.03). Only CIT administration (1 g/kg) was able to restore MPS (CIT1: 3.4 ± 0.3 vs. R: 2.5 ± 0.2 %/day, p = 0.05) and increase muscle maximum tetanic force (CIT1: 441 ± 15 vs. R: 392 ± 22 g, p = 0.05) and muscle strength (CIT1: 4,259 ± 478 vs. R: 3,045 ± 663 A.U., p = 0.05). LEU had no effect and CIT + LEU supplementation had few effects, limited to adipose mass and fatigue force. The results of this study highlight the ability of CIT alone to preserve muscle function during dietary restriction. Surprisingly, LEU antagonized some effects of CIT. The mechanisms involved in this antagonistic effect warrant further study.