Neutral lipid storage disease with myopathy and myotonia associated to pathogenic variants on PNPLA2 and CLCN1 genes: case report.

BACKGROUND: Neutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy predominantly proximal in the shoulder girdle. Clinical myotonia is uncommon. We will report a rare case of association of pathogenic variants on PNPLA2 and CLCN1 genes with a mixed phenotype of NLSD-M and a subclinical form of Thomsen's congenital myotonia. CASE PRESENTATION: We describe a patient with chronic proximal myopathy, subtle clinical myotonia and electrical myotonia on electromyography (EMG). Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL). A blood smear analysis showed Jordan's anomaly, a hallmark of NLSD-M. A genetic panel was collected using next-generation sequencing (NGS) technique, which identified two pathogenic variants on genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia, whose association has not been previously described. CONCLUSIONS: Although uncommon, it is important to remember the possibility of association of pathogenic variants to explain a specific neuromuscular disease phenotype. The use of a range of complementary methods, including myopathy genetic panels, may be essential to diagnostic definition in such cases.

Ichthyosis, cataracts, and motor delay in an infant: A case of Chanarin-Dorfman syndrome.

Chanarin-Dorfman syndrome (CDS) is a rare, autosomal recessive disorder of impaired triacylglycerol catabolism leading to cytoplasmic deposition of triglycerides in various cell types. We describe the case of an 8-month-old boy with cataracts, strabismus, motor delays, and an ichthyosiform rash since birth. Genetic testing revealed a pathogenic variant of the ABHD5 gene, suggestive of CDS, and further workup demonstrated hepatic steatosis and myopathy. His ichthyosis improved with initiation of a diet low in very long-chain fatty acids and medium-chain fatty acid supplementation.

Mushroom supplements triggering a flare of HMGCR immune mediated necrotising myopathy.

Hydroxyl-methyl-glutaryl-Co-A reductase (HMGCR) immune mediated necrotising myopathy (IMNM) is a rare autoimmune myositis that is thought to be triggered by statins and responds to immunomodulation. We report a case of a woman in her 30s with HMGCR IMNM without a history of statin exposure who had a clear flare of her myositis after beginning mushroom supplements. Mushrooms are natural HMGCR inhibitors, and this is the first case to demonstrate a flare triggered by mushrooms in a patient with known HMGCR IMNM. This case highlights the importance of reviewing diet and supplements in patients with IMNM. It also emphasises the importance of strict statin avoidance for patients with IMNM even when the myositis is under good control.

Comparative study on molecular mechanism of diabetic myopathy in two different types of streptozotocin-induced diabetic models.

AIMS: Streptozotocin (STZ)-induced diabetic animal models have been widely used to study diabetic myopathy; however, non-specific cytotoxic effects of high-dose STZ have been discussed. The purpose of this study was to compare diabetic myopathy in a high-STZ model with another well-established STZ model with reduced cytotoxicity (high-fat diet (HFD) and low-dose STZ) and to identify mechanistic insights underlying diabetic myopathy in STZ models that can mimic perturbations observed in human patients with diabetic myopathy. MAIN METHODS: Male C57BL6 mice were injected with a single high dose of STZ (180 mg/kg, High-STZ) or were given HFD plus low-dose STZ injection (STZ, 55 mg/kg/day, five consecutive days, HFD/STZ). We characterized diabetic myopathy by histological and immunochemical analyses and conducted gene expression analysis. KEY FINDINGS: The high-STZ model showed a significant reduction in tibialis anterior myofiber size along with decreased satellite cell content and downregulation of inflammation response and collagen gene expression. Interestingly, blood corticosteroid levels were significantly increased in the high-STZ model, which was possibly related to lowered inflammation response-related gene expression. Further analyses using the HFD/STZ model showed downregulation of gene expression related to mitochondrial functions accompanied by a significant decrease in ATP levels in the muscles. SIGNIFICANCE: The high-STZ model is suitable for studies regarding not only severe diabetic myopathy with excessive blood glucose but also negative impact of glucocorticoids on skeletal muscles. In contrast, the HFD/STZ model is characterized by higher immune responses and lower ATP production, which also reflects the pathologies observed in human diabetic patients.

Protective effects of dietary curcumin and astaxanthin against heat-induced ROS production and skeletal muscle injury in male and female C57BL/6J mice.

AIMS: This study aimed to: 1) investigate sex differences in heat-induced mitochondrial dysfunction, ROS production, and skeletal muscle injury in mice; 2) evaluate whether curcumin and astaxanthin, alone or together, would prevent those heat-induced changes. MAIN METHODS: Male and female C57BL/6J mice were treated with curcumin and astaxanthin for 10 days, then exposed to 39.5 °C heat for up to 3 h. Heat-induced hyperthermia, changes in mitochondrial morphology and function, and oxidative damage to skeletal muscle were evaluated. KEY FINDINGS: Although female mice had a slightly higher basal core body temperature (Tc) than male mice, peak Tc during heat exposure was significantly lower in females than in males. Heat increased ROS levels in skeletal muscle in both sexes; interestingly, the increases in ROS were greater in females than in males. Despite the above-mentioned differences, heat induced similar levels of mitochondrial fragmentation and membrane potential depolarization, caspase 3/7 activation, and injury in male and female skeletal muscle. Individual treatment of curcumin or astaxanthin did not affect basal and peak Tc but prevented heat-induced mitochondrial dysfunction, ROS increases, and apoptosis in a dose-dependent manner. Moreover, a low-dose combination of curcumin and astaxanthin, which individually showed no effect, reduced the heat-induced oxidative damage to skeletal muscle. SIGNIFICANCE: Both male and female mice can develop mitochondrial dysfunction and oxidative stress in skeletal muscle when exposed to heat stress. High doses of either curcumin or astaxanthin limit heat-induced skeletal muscle injury, but a low-dose combination of these ingredients may increase their efficacy.

Improper Remodeling of Organelles Deputed to Ca2+ Handling and Aerobic ATP Production Underlies Muscle Dysfunction in Ageing.

Proper skeletal muscle function is controlled by intracellular Ca2+ concentration and by efficient production of energy (ATP), which, in turn, depend on: (a) the release and re-uptake of Ca2+ from sarcoplasmic-reticulum (SR) during excitation-contraction (EC) coupling, which controls the contraction and relaxation of sarcomeres; (b) the uptake of Ca2+ into the mitochondrial matrix, which stimulates aerobic ATP production; and finally (c) the entry of Ca2+ from the extracellular space via store-operated Ca2+ entry (SOCE), a mechanism that is important to limit/delay muscle fatigue. Abnormalities in Ca2+ handling underlie many physio-pathological conditions, including dysfunction in ageing. The specific focus of this review is to discuss the importance of the proper architecture of organelles and membrane systems involved in the mechanisms introduced above for the correct skeletal muscle function. We reviewed the existing literature about EC coupling, mitochondrial Ca2+ uptake, SOCE and about the structural membranes and organelles deputed to those functions and finally, we summarized the data collected in different, but complementary, projects studying changes caused by denervation and ageing to the structure and positioning of those organelles: a. denervation of muscle fibers-an event that contributes, to some degree, to muscle loss in ageing (known as sarcopenia)-causes misplacement and damage: (i) of membrane structures involved in EC coupling (calcium release units, CRUs) and (ii) of the mitochondrial network; b. sedentary ageing causes partial disarray/damage of CRUs and of calcium entry units (CEUs, structures involved in SOCE) and loss/misplacement of mitochondria; c. functional electrical stimulation (FES) and regular exercise promote the rescue/maintenance of the proper architecture of CRUs, CEUs, and of mitochondria in both denervation and ageing. All these structural changes were accompanied by related functional changes, i.e., loss/decay in function caused by denervation and ageing, and improved function following FES or exercise. These data suggest that the integrity and proper disposition of intracellular organelles deputed to Ca2+ handling and aerobic generation of ATP is challenged by inactivity (or reduced activity); modifications in the architecture of these intracellular membrane systems may contribute to muscle dysfunction in ageing and sarcopenia.

Coenzyme Q nanodisks counteract the effect of statins on C2C12 myotubes.

Depletion of coenzyme Q (CoQ) is associated with disease, ranging from myopathy to heart failure. To induce a CoQ deficit, C2C12 myotubes were incubated with high dose simvastatin. This resulted in a concentration-dependent inhibition of cell viability. Simvastatin-induced effects were prevented by co-incubation with mevalonic acid. When myotubes were incubated with 60 µM simvastatin, mitochondrial CoQ content decreased while co-incubation with CoQ nanodisks (ND) increased mitochondrial CoQ levels and improved cell viability. Incubation of myotubes with simvastatin also led to a reduction in oxygen consumption rate (OCR). When myotubes were co-incubated with simvastatin and CoQ ND, the decline in OCR was ameliorated. The data indicate that CoQ ND represent a water soluble vehicle capable of delivering CoQ to cultured myotubes. Thus, these biocompatible nanoparticles have the potential to bypass poor CoQ oral bioavailability as a treatment option for individuals with severe CoQ deficiency syndromes and/or aging-related CoQ depletion.

Skeletal myopathy in CKD: a comparison of adenine-induced nephropathy and 5/6 nephrectomy models in mice.

Preclinical animal models of chronic kidney disease (CKD) are critical to investigate the underlying mechanisms of disease and to evaluate the efficacy of novel therapeutics aimed to treat CKD-associated pathologies. The objective of the present study was to compare the adenine diet and 5/6 nephrectomy (Nx) CKD models in mice. Male and female 10-wk-old C57BL/6J mice (n = 5-9 mice/sex/group) were randomly allocated to CKD groups (0.2-0.15% adenine-supplemented diet or 5/6 Nx surgery) or the corresponding control groups (casein diet or sham surgery). Following the induction of CKD, the glomerular filtration rate was reduced to a similar level in both adenine and 5/6 Nx mice (adenine diet-fed male mice: 81.1 ± 41.9 µL/min vs. 5/6 Nx male mice: 160 ± 80.9 µL/min, P = 0.5875; adenine diet-fed female mice: 112.9 ± 32.4 µL/min vs. 5/6 Nx female mice: 107.0 ± 45.7 µL/min, P = 0.9995). Serum metabolomics analysis indicated that established uremic toxins were robustly elevated in both CKD models, although some differences were observed between CKD models (i.e., p-cresol sulfate). Dysregulated phosphate homeostasis was observed in the adenine model only, whereas Ca2+ homeostasis was disturbed in male mice with both CKD models. Compared with control mice, muscle mass and myofiber cross-sectional areas of the extensor digitorum longus and soleus muscles were ∼18-24% smaller in male CKD mice regardless of the model but were not different in female CKD mice (P > 0.05). Skeletal muscle mitochondrial respiratory function was significantly decreased (19-24%) in CKD mice in both models and sexes. These findings demonstrate that adenine diet and 5/6 Nx models of CKD have similar levels of renal dysfunction and skeletal myopathy. However, the adenine diet model demonstrated superior performance with regard to mortality (∼20-50% mortality for 5/6 Nx vs. 0% mortality for the adenine diet, P < 0.05 for both sexes) compared with the 5/6 Nx surgical model.NEW & NOTEWORTHY Numerous preclinical models of chronic kidney disease have been used to evaluate skeletal muscle pathology; however, direct comparisons of popular models are not available. In this study, we compared adenine-induced nephropathy and 5/6 nephrectomy models. Both models produced equivalent levels of muscle atrophy and mitochondrial impairment, but the adenine model exhibited lower mortality rates, higher consistency in uremic toxin levels, and dysregulated phosphate homeostasis compared with the 5/6 nephrectomy model.

L-carnitine supplementation for muscle weakness and fatigue in children with neurofibromatosis type 1: A Phase 2a clinical trial.

Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L-carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L-carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12-week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L-carnitine. Primary outcomes were safety (self-reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6-minute-walk test [6MWT]), and parent-reported questionnaires (PedsQL™, CBCL/6-18). Six children completed the trial with no self-reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89-60.75; p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99-134.1; p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97-16.03; p = 0.01) and 6MWT distance (95% CI 5.88-75.45; p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z-score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of individuals remaining on L-carnitine after the study. Twelve weeks of L-carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment.

Melatonin role in skeletal muscle disorders.

OBJECTIVE: This review discusses the impact of the neuro-hormone melatonin on skeletal muscle disorders based on recent literature data with the aim to clarify the utility of the melatonin therapy in patients affected by muscle diseases. MATERIALS AND METHODS: It has been pointed out the possible role of melatonin as a food supplement to cure muscular disorders characterized by muscle wasting. Oxidative damage has been proposed as one of the major contributors of the skeletal muscle decline occurring both in physiological and pathological conditions. It is known that excessive oxidant levels lead to mitochondrial damage, and in turn, contribute to apoptotic signaling activation and autophagic impairment. This condition is common in a variety of skeletal muscle disorders. RESULTS: The scientific evidence enhances the antioxidant effect of melatonin, that has been demonstrated by several studies both in vitro and in vivo. This effect counteracts mitochondrial impairments and reduces oxidative stress and autophagic alterations in muscle fibers. Its beneficial role in restoring muscle decline, takes place mainly in atrophic conditions correlated to muscle aging. CONCLUSIONS: The findings of the research suggest that melatonin may be considered as a valid dietary supplement, useful to prevent muscle wasting, in particular, in sarcopenia-associated diseases.

Bezafibrate activation of PPAR drives disturbances in mitochondrial redox bioenergetics and decreases the viability of cells from patients with VLCAD deficiency.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common inborn long-chain fatty acid oxidation (FAO) disorder. VLCAD deficiency is characterized by distinct phenotypes. The severe phenotypes are potentially life-threatening and affect the heart or liver, with a comparatively milder phenotype characterized by myopathic symptoms. There is an unmet clinical need for effective treatment options for the myopathic phenotype. The molecular mechanisms driving the gradual decrease in mitochondrial function and associated alterations of muscle fibers are unclear. The peroxisome proliferator-activated receptor (PPAR) pan-agonist bezafibrate is a potent modulator of FAO and multiple other mitochondrial functions and has been proposed as a potential medication for myopathic cases of long-chain FAO disorders. In vitro experiments have demonstrated the ability of bezafibrate to increase VLCAD expression and activity. However, the outcome of small-scale clinical trials has been controversial. We found VLCAD deficient patient fibroblasts to have an increased oxidative stress burden and deranged mitochondrial bioenergetic capacity, compared to controls. Applying heat stress under fasting conditions to bezafibrate pretreated patient cells, caused a marked further increase of mitochondrial superoxide levels. Patient cells failed to maintain levels of the essential thiol peptide antioxidant glutathione and experienced a decrease in cellular viability. Our findings indicate that chronic PPAR activation is a plausible initiator of long-term pathogenesis in VLCAD deficiency. Our findings further implicate disruption of redox homeostasis as a key pathogenic mechanism in VLCAD deficiency and support the notion that a deranged thiol metabolism might be an important pathogenic factor in VLCAD deficiency.

Defective endoplasmic reticulum-mitochondria contacts and bioenergetics in SEPN1-related myopathy.

SEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired.

Role of anthraquinones in Cassia occidentalis induced hepato-myo-encephalopathy.

ETHNOPHARMACOLOGICAL RELEVANCE: The different plant parts of Cassia occidentalis Linn, (CO) such as root, leaves, seeds and pods have traditionally been used in multifarious medicines for the treatment of dysentery, diarrhea, constipation, fever, eczema, cancer and venereal diseases. MATERIALS AND METHODS: A systematic search of literature has been done in books and scientific databases like Science Direct, Pubmed, Google Scholar and Scopus etc. These sources were used to compile, analyze and review the information regarding the phytochemistry, toxicology and mechanism of toxicity of CO. The various references on this subject are cited in our review ranging from 1956 to 2019. RESULTS: Unintentional exposure of CO causes serious pathological condition in children, known as hepato-myo-encephalopathy (HME). The toxicity after CO consumption is associated with the presence of anthraquinones (AQs), a class of secondary plant metabolites. These AQs at high concentrations are known to cause detrimental effects on essential vital organs such as liver, kidney, spleen, brain, muscle and reproductive organs. The animal studies in rodent models as well as clinical investigations have clearly revealed that CO toxicity is associated with enhanced hepatotoxicity serum markers (ALT, AST, and LDH) and presence of necrotic lesions in liver. Furthermore, CO also causes vacuolization in muscle tissue and increases the level of CPK which is a prominent muscle damage marker. Apart from these target organs, CO consumption also causes neuronal damage via disturbing the levels of different proteins such as (GFAP and b-tubulin III). The mechanistic studies show that AQs present in CO have the potential to disturb the cellular homeostasis via binding to DNA, increasing the production ROS and showing inhibitory effects on essential enzymes etc. Therefore, AQs have been observed to be the primary culprit agents contributing to the toxicity of CO in children and animals. CONCLUSION: Despite its therapeutic potential, CO consumption can be detrimental if consumed in high amounts. A thorough analysis of literature reveals that AQs are the primary factors contributing to toxicity of CO seeds. Exposure to CO seeds causes HME, which is a serious life threatening condition for the malnourished children from lower strata. Multiple mechanisms are involved in the CO induced HME in patients. Lack of appropriate diagnostic measures and a poor understanding of the CO toxicity mechanism in humans and animals complicate the clinical management of CO poisoning subjects. Therefore, development of point of care diagnostic kits shall help in early diagnosis & suitable management of CO poisoning.

Nutrition management guideline for very-long chain acyl-CoA dehydrogenase deficiency (VLCAD): An evidence- and consensus-based approach.

The nutrition management guideline for very-long chain acyl-CoA dehydrogenase deficiency (VLCAD) is the fourth in a series of web-based guidelines focusing on the diet treatment for inherited metabolic disorders and follows previous publication of guidelines for maple syrup urine disease (2014), phenylketonuria (2016) and propionic acidemia (2019). The purpose of this guideline is to establish harmonization in the treatment and monitoring of individuals with VLCAD of all ages in order to improve clinical outcomes. Six research questions were identified to support guideline development on: nutrition recommendations for the healthy individual, illness management, supplementation, monitoring, physical activity and management during pregnancy. This report describes the methodology used in its development including review, critical appraisal and abstraction of peer-reviewed studies and unpublished practice literature; expert input through two Delphi surveys and a nominal group process; and external review from metabolic physicians and dietitians. It includes the summary statements of the nutrition management recommendations for each research question, followed by a standardized rating based on the strength of the evidence. Online, open access of the full published guideline allows utilization by health care providers, researchers and collaborators who advise, advocate and care for individuals with VLCAD and their families and can be accessed from the Genetic Metabolic Dietitians International (https://GMDI.org) and Southeast Regional Genetics Network (https://southeastgenetics.org/ngp) websites.

Impact of alpha-tocopherol deficiency and supplementation on sacrocaudalis and gluteal muscle fiber histopathology and morphology in horses.

BACKGROUND: A subset of horses deficient in alpha-tocopherol (α-TP) develop muscle atrophy and vitamin E-responsive myopathy (VEM) characterized by mitochondrial alterations in the sacrocaudalis dorsalis medialis muscle (SC). OBJECTIVES: To quantify muscle histopathologic abnormalities in subclinical α-TP deficient horses before and after α-TP supplementation and compare with retrospective (r)VEM cases. ANIMALS: Prospective study; 16 healthy α-TP-deficient Quarter Horses. Retrospective study; 10 retrospective vitamin E-responsive myopathy (rVEM) cases . METHODS: Blood, SC, and gluteus medius (GM) biopsy specimens were obtained before (day 0) and 56 days after 5000 IU/450 kg horse/day PO water dispersible liquid α-TP (n = 8) or control (n = 8). Muscle fiber morphology and mitochondrial alterations were compared in samples from days 0 and 56 and in rVEM cases. RESULTS: Mitochondrial alterations more common than our reference range (<2.5% affected fibers) were present in 3/8 control and 4/8 treatment horses on day 0 in SC but not in GM (mean, 2.2; range, 0%-10% of fibers). Supplementation with α-TP for 56 days did not change the percentage of fibers with mitochondrial alterations or anguloid atrophy, or fiber size in GM or SC. Clinical rVEM horses had significantly more mitochondrial alterations (rVEM SC, 13% ± 7%; GM, 3% ± 2%) and anguloid atrophy compared to subclinical day 0 horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Clinically normal α-TP-deficient horses can have mitochondrial alterations in the SC that are less severe than in atrophied VEM cases and do not resolve after 56 days of α-TP supplementation. Preventing α-TP deficiency may be of long-term importance for mitochondrial viability.

Cardiac function and incidence of unexplained myocardial scarring in patients with primary carnitine deficiency - a cardiac magnetic resonance study.

Primary carnitine deficiency (PCD) not treated with L-Carnitine can lead to sudden cardiac death. To our knowledge, it is unknown if asymptomatic patients treated with L-Carnitine suffer from myocardial scarring and thus be at greater risk of potentially serious arrhythmia. Cardiac evaluation of function and myocardial scarring is non-invasively best supported by cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE). The study included 36 PCD patients, 17 carriers and 17 healthy subjects. A CMR cine stack in the short-axis plane were acquired to evaluate left ventricle (LV) systolic and diastolic function and a similar LGE stack to evaluate myocardial scarring and replacement fibrosis. LV volumes and ejection fraction were not different between PCD patients, carriers and healthy subjects. However, LV mass was higher in PCD patients with the severe homozygous mutation, c.95 A > G (p = 0.037; n = 17). Among homozygous PCD patients there were two cases of unexplained myocardial scarring and this is in contrast to no myocardial scarring in any of the other study participants (p = 0.10). LV mass was increased in PCD patients. L-carnitine supplementation is essential in order to prevent potentially lethal cardiac arrhythmia and serious adverse cardiac remodeling.

Dietary potassium and available phosphorous on broiler growth performance, carcass characteristics, and wooden breast.

Broiler dietary potassium (K) and available phosphorous (AvP) have decreased in recent years but both ions are intimately involved in the elimination of hydrogen ions that are produced during rapid growth. It was hypothesized that the decrease of these dietary electrolytes was related to the development of myopathies, and thus increased dietary K and/or AvP would reduce the occurrence of breast myopathies. A total of 320 Ross male broiler chicks were placed into 16 pens and fed 2 diet series containing either decreasing AvP levels of 0.45, 0.40, and 0.35% in the starter, grower, and finisher diets, respectively (Decline), or a fixed AvP of 0.45% in all dietary phases (Fixed). To complete a 2 × 2 design either normal basal dietary K (K-) (0.86, 0.77, 0.68%) or added dietary K (K+) (1.01, 0.93, 0.88%) were also applied to starter, grower, and finisher diets, respectively. Blood physiology was measured at 29 and 42 d. Carcass data, wooden breast and white striping scores were measured at 35 and 43 d. The K+ diets improved feed conversion ratio at 35 d (1.52 vs 1.57 g: g), reduced body weight at 42 d (3524 vs 3584 g), reduced hemoglobin (6.83 vs 7.58 g/dL), and packed cell volume (20.1 vs 22.3%) at 29 d, reduced ionized blood calcium (1.42 vs 1.47 mmol/L) at 42 d, and reduced partial pressure of blood CO2 (49.1 vs 54.7 mm/Hg) at 42 d relative to broilers fed basal K- diets (P < 0.05). Fixed AvP diets improved feed conversion ratio at 28 and 42 d, increased percentage breast meat (28.85 vs 27.58%) and carcass water pickup (2.72 vs 1.42%) at 35 d, and reduced wooden breast (2.88 vs 3.69) at 43 d (P < 0.05).

Dietary amino acids under hypoxic conditions exacerbates muscle myopathies including wooden breast and white stripping.

The occurrence of wooden breast (WB) and white striping (WS) of broiler breast myopathies may be associated with least-cost feed formulations and the inclusion of greater amounts of synthetic amino acids. Two experiments were conducted to evaluate the effects of supplemental glutamine (Gln-/+, 0 and 1%) and arginine (Arg-/+, 0 and 0.25%) in a 2 × 2 factorial arrangement. Experiment 1 consisted of 8 replicates using 32 pens and focused on live performance to 44 d of age, carcass yield, and meat quality evaluations at 45 d of age. Live performance parameters including feed intake, BW gain, mortality, and feed conversion were evaluated. Post-harvest carcass yield, breast muscle quality (including WB and WS), proximate analysis, and mineral analysis of breast muscle and tibia bone were also evaluated. Experiment 2 comprised 4 replicates using 8 pens with weekly measurements of blood physiology and muscle myopathy development from 21 to 45 d of age. Broilers fed supplemental Gln and Arg (Gln+/Arg+) produced broilers with greater BW and improved FCR. The WB and WS severity increased with Gln+ diets, while only WB increased using Arg+ diets. Weekly observations revealed the greatest increase in WB myopathies occurred between 28 to 35 d, while WS significantly increased one week later (35 to 42 d). When comparing broilers of similar BW at 45 d, Gln+ diets resulted in greater WS scores and percentage breast muscle fat. Further analysis of WB and WS scores (independent of treatment affect) revealed that increased myopathy scores were associated with increased blood CO2, H2CO3, and reduced O2 with increased meat pH, moisture content, and Ca concentration. These results indicated that increased muscle Ca is associated with increased WB, while increased dietary glutamine and lack of oxygen may have resulted in a reverse flux of the citric acid cycle and reduced electron transport chain activity resulting in increased WS.

Redox correlation in muscle lengthening and immune response in eccentric exercise.

This study was designed to examine the potential involvement of reactive oxygen species in skeletal muscle dysfunction linked with stretching in a mouse model and to explore the effects of combined antioxidant intake on peripheral leukocyte apoptosis following eccentrically-biased downhill runs in human subjects. In the mouse model, diaphragmatic muscle was stretched by 30% of its optimal length, followed by 5-min contraction. Muscle function and extracellular reactive oxygen species release was measured ex vivo. In human models, participants performed two trials of downhill running either with or without antioxidant supplementation, followed by apoptotic assay of inflammatory cells in the blood. The results showed that stretch led to decreased muscle function and prominent ROS increase during muscle contraction. In human models, we observed an elevation in circulating leukocyte apoptosis 24-48 hours following acute downhill runs. However, there is an attenuated leukocyte apoptosis following the second bout of downhill run. Interestingly, the combination of ascorbic acid (vitamin C) and α-tocopherol (vitamin E) supplementation attenuated the decrease in B-cell lymphoma 2 (Bcl-2) at 24 hours following acute downhill running. These data collectively suggest that significant ROS formation can be induced by muscle-lengthening associated with eccentric exercise, which is accompanied by compromised muscle function. The combination of antioxidants supplementation appears to have a protective role via the attenuation of decrease in anti-apoptotic protein.