Muscle Metabolic Disorders Research Articles

The Effect of Aerobic Exercise on SREBP-1c Gene Expression in Skeletal Muscle in Obese Female Rats

Background: Obesity causes skeletal muscle metabolic disorders by altering the expression of the genes involved in lipid metabolism. One of the genes that play an important role in lipid metabolism in skeletal muscle tissue is sterol regulatory element binding protein (SREBP). Objectives: Since the interacting effect of aerobic exercise and high-fat diet on the expression of this gene has not been well studied, the aim of the present study was to determine the effect of aerobic exercise on the expression of the SREBP-1c gene in skeletal muscle in obese female rats. Methods: Eighteen female Wistar rats in the weight range of 180 - 200 grams were selected and randomly divided into three groups: (1) control fed with a normal diet; (2) control fed with a high-fat diet; and (3) aerobic exercise plus a high-fat diet. The high-fat diet contained 40% fat (20% soybean oil and 20% animal fat), 13% protein, and 47% carbohydrates. The rats were initially fed with a high-fat diet for 6 weeks, and then they performed aerobic exercise on a treadmill 5 times a week for 6 weeks. Forty-eight hours after the last training session and after eleven hours of fasting, the rats were anesthetized with ketamine and xylazine. Quadriceps tissues were removed to determine the SREBP-1c gene’s expression by real-time PCR. Results: Feeding with a high-fat diet significantly increased the weight of rats (P = 0.001). The expression of the SREBP-1c gene in the group fed with the high-fat diet decreased significantly compared to the group fed with the normal diet (P = 0.001). Aerobic exercise significantly increased the expression of the SREBP-1c gene in the quadriceps muscle (P = 0.001), contradicting the effect of the high-fat diet on the expression of this gene. Conclusions: Aerobic training may alleviate lipid metabolism disorders in muscles by increasing the expression of the SREBP-1c gene. Therefore, aerobic exercises can be used to contradict the metabolic complications caused by the high-fat diet in skeletal muscles.

The role of Huidouba in regulating skeletal muscle metabolic disorders in prediabetic mice through AMPK/PGC-1α/PPARα pathway

Prediabetes is a transitional state between normal blood glucose levels and diabetes, but it is also a reversible process. At the same time, as one of the most important tissues in the human body, the metabolic disorder of skeletal muscle is closely related to prediabetes. Huidouba (HDB) is a clinically proven traditional Chinese medicine with significant effects in regulating disorders of glucose and lipid metabolism. Our study aimed to investigate the efficacy and mechanism of HDB in prediabetic model mice from the perspective of skeletal muscle. C57BL/6J mice (6 weeks old) were fed a high-fat diet (HFD) for 12 weeks to replicate the prediabetic model. Three concentrations of HDB were treated with metformin as a positive control. After administration, fasting blood glucose was measured as an indicator of glucose metabolism, as well as lipid metabolism indicators such as total triglyceride (TG), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), free fatty acid (FFA), and lactate dehydrogenase (LDH). Muscle fat accumulation and glycogen accumulation were observed. The protein expression levels of p-AMPK, AMPK, PGC-1α, PPAR-α, and GLUT-4 were detected. After HDB treatment, fasting blood glucose was significantly improved, and TG, LDL-C, FFA, and LDH in serum and lipid accumulation in muscle tissue were significantly reduced. In addition, HDB significantly upregulated the expression levels of p-AMPK/AMPK, PGC-1α, PPAR-α, and GLUT-4 in muscle tissue. In conclusion, HDB can alleviate the symptoms of prediabetic model mice by promoting the AMPK/PGC-1α/PPARα pathway and upregulating the expression of GLUT-4 protein.

Growth arrest and DNA damage-inducible alpha regulates muscle repair and fat infiltration through ATP synthase F1 subunit alpha.

Skeletal muscle fat infiltration is a common feature during ageing, obesity and several myopathies associated with muscular dysfunction and sarcopenia. However, the regulatory mechanisms of intramuscular adipogenesis and strategies to reduce fat infiltration in muscle remain unclear. Here, we identified the growth arrest and DNA damage-inducible alpha (GADD45A), a stress-inducible histone folding protein, as a critical regulator of intramuscular fat (IMAT) infiltration. To explore the role of GADD45A on IMAT infiltration and muscle regeneration, the gain or loss function of GADD45A in intramuscular preadipocytes was performed. The adipocyte-specific GADD45A knock-in (KI) mice and high IMAT-infiltrated muscle model by glycerol injection (50μL of 50% v/v GLY) were generated. RNA-sequencing, histological changes, gene expression, lipid metabolism, mitochondrial function and the effect of dietary factor epigallocatechin-3-gallate (EGCG) treatment (100mg/kg) on IMAT infiltration were studied. The unbiased transcriptomics data analysis indicated that GADD45A expression positively correlates with IMAT infiltration and muscle metabolic disorders in humans (correlation: young vs. aged people, Gadd45a and Cebpa, r2 =0.20, P<0.05) and animals (correlation: wild-type [WT] vs. mdx mice, Gadd45a and Cebpa, r2 =0.38, P<0.05; NaCl vs. GLY mice, Gadd45a and Adipoq/Fabp4, r2 =0.80/0.71, both P<0.0001). In vitro, GADD45A overexpression promotes intramuscular preadipocyte adipogenesis, upregulating the expression of adipogenic genes (Ppara: +47%, Adipoq: +28%, P<0.001; Cebpa: +135%, Fabp4: +16%, P<0.01; Pparg: +66%, Leptin: +77%, P<0.05). GADD45A knockdown robustly decreased lipid accumulation (Pparg: -57%, Adipoq: -35%, P<0.001; Fabp4: -37%, P<0.01; Leptin: -28%, P<0.05). GADD45A KI mice exhibit inhibited skeletal muscle regeneration (myofibres: -40%, P<0.01) and enhanced IMAT infiltration (adipocytes: +20%, P<0.05). These KI mice have impaired exercise endurance and mitochondrial function. Mechanistically, GADD45A affects ATP synthase F1 subunit alpha (ATP5A1) ubiquitination degradation (ubiquitinated ATP5A1, P<0.001) by recruiting the E3 ubiquitin ligase TRIM25, which decreases ATP synthesis (ATP production: -23%, P<0.01) and inactivates the cAMP/PKA/LKB1 signalling pathway (cAMP: -36%, P<0.01; decreased phospho-PKA and phospho-LKB1 protein content, P<0.01). The dietary factor EGCG can protect against muscle fat infiltration (triglyceride: -64%, P<0.05) via downregulating GADD45A (decreased GADD45A protein content, P<0.001). Our findings reveal a crucial role of GADD45A in regulating muscle repair and fat infiltration and suggest that inhibition of GADD45A by EGCG might be a potential strategy to combat fat infiltration and its associated muscle dysfunction.

Exercise activates autophagy and regulates endoplasmic reticulum stress in muscle of high-fat diet mice to alleviate insulin resistance

Exercise training has been demonstrated as an effective therapy for insulin resistance (IR) to relieve skeletal muscle metabolic disorders. Physiologic protective autophagy was found blocked by IR induced severe endoplasmic reticulum (ER) stress, which may lead to progression of IR. However, the mechanisms are not fully understood. Therefore, this study sought to investigate that how exercise training act on IR through an exploration into the mechanism of ER stress and high-fat diet (HFD)-blocked autophagy. A rodent model was adopted in mice via a HFD and an 8-week swim exercise training intervention. The mouse IR model was successfully established through HFD treatment: body mass, adipose weight, HOMA-IR index increased, as well as IRS1, inhibited in the muscle of HFD mice. Moreover, the AMPK/PGC1α pathway was depressed and IRE1, PERK, ATF6-related ER stress signaling was activated in the muscle of HFD mice. While autophagy factors, including BNIP3, LC3II/LC3I, and PINK1, decreased. However, additional 8-week exercise training during HFD was found to reverse all these changes and alleviate IR. Thus, exercise training could facilitate HFD-blocked protective autophagy via the activation of the AMPK/PGC1α pathway to relieve insulin resistance in mice. Our study provides experimental data for the prevention of T2DM and insulin resistance.

Untargeted Metabolomic Characteristics of Skeletal Muscle Dysfunction in Rabbits Induced by a High Fat Diet.

Simple SummaryIn the present study, we performed an untargeted metabolomic analysis of skeletal muscle of rabbits and found that the skeletal muscle of rabbits fed a high-fat diet is rich in many metabolites, most of which are associated with type 2 diabetes and metabolic syndrome. In this paper, the mechanism of action of these metabolites in skeletal muscle and the metabolic pathways that interfere with the normal operation mechanism of the body are described and presented in the form of charts. Finally, we found that skeletal muscle-rich phospholipids, long-chain carnitine, histidine, carnosine, and tetrahydrocortisone may be potential markers for type 2 diabetes and metabolic syndrome, and may serve as potential therapeutic targets for related diseases in the future.Type 2 diabetes and metabolic syndrome caused by a high fat diet (HFD) have become public health problems worldwide. These diseases are characterized by the oxidation of skeletal muscle mitochondria and disruption of insulin resistance, but the mechanisms are not well understood. Therefore, this study aims to reveal how high-fat diet causes skeletal muscle metabolic disorders. In total, 16 weaned rabbits were randomly divided into two groups, one group was fed a standard normal diet (SND) and the other group was fed a high fat diet (HFD) for 5 weeks. At the end of the five-week experiment, skeletal muscle tissue samples were taken from each rabbit. Untargeted metabolomic analysis was performed using ultra-performance liquid chromatography combined with mass spectrometry (UHPLC-MS/MS). The results showed that high fat diet significantly altered the expression levels of phospholipids, LCACs, histidine, carnosine, and tetrahydrocorticosterone in skeletal muscle. Principal component analysis (PCA) and least squares discriminant analysis (PLS-DA) showed that, compared with the SND group, skeletal muscle metabolism in HFD group was significantly up-regulated. Among 43 skeletal muscle metabolites in the HFD group, phospholipids, LCACs, histidine, carnosine, and tetrahydrocorticosteroids were identified as biomarkers of skeletal muscle metabolic diseases, and may become potential physiological targets of related diseases in the future. Untargeted metabonomics analysis showed that high-fat diet altered the metabolism of phospholipids, carnitine, amino acids and steroids in skeletal muscle of rabbits. Notably, phospholipids, LCACs, histidine, carnopeptide, and tetrahydrocorticosteroids block the oxidative capacity of mitochondria and disrupt the oxidative capacity of glucose and the fatty acid-glucose cycle in rabbit skeletal muscle.

Chest MRI to diagnose early diaphragmatic weakness in Pompe disease

BackgroundIn Pompe disease, an inherited metabolic muscle disorder, severe diaphragmatic weakness often occurs. Enzyme replacement treatment is relatively ineffective for respiratory function, possibly because of irreversible damage to the diaphragm early in the disease course. Mildly impaired diaphragmatic function may not be recognized by spirometry, which is commonly used to study respiratory function. In this cross-sectional study, we aimed to identify early signs of diaphragmatic weakness in Pompe patients using chest MRI.MethodsPompe patients covering the spectrum of disease severity, and sex and age matched healthy controls were prospectively included and studied using spirometry-controlled sagittal MR images of both mid-hemidiaphragms during forced inspiration. The motions of the diaphragm and thoracic wall were evaluated by measuring thoracic cranial-caudal and anterior–posterior distance ratios between inspiration and expiration. The diaphragm shape was evaluated by measuring the height of the diaphragm curvature. We used multiple linear regression analysis to compare different groups.ResultsWe included 22 Pompe patients with decreased spirometry results (forced vital capacity in supine position < 80% predicted); 13 Pompe patients with normal spirometry results (forced vital capacity in supine position ≥ 80% predicted) and 18 healthy controls. The mean cranial-caudal ratio was only 1.32 in patients with decreased spirometry results, 1.60 in patients with normal spirometry results and 1.72 in healthy controls (p < 0.001). Anterior–posterior ratios showed no significant differences. The mean height ratios of the diaphragm curvature were 1.41 in patients with decreased spirometry results, 1.08 in patients with normal spirometry results and 0.82 in healthy controls (p = 0.001), indicating an increased curvature of the diaphragm during inspiration in Pompe patients.ConclusionsEven in early-stage Pompe disease, when spirometry results are still within normal range, the motion of the diaphragm is already reduced and the shape is more curved during inspiration. MRI can be used to detect early signs of diaphragmatic weakness in patients with Pompe disease, which might help to select patients for early intervention to prevent possible irreversible damage to the diaphragm.

Miopatías metabólicas, mitocondriales y tóxicas

Metabolic and mitochondrial myopathies are inherited disorders characterized by incompetence to provide energy substrate (ATP) from nutrients. Both carbohydrate or lipid metabolism or mitochondrial oxidative phosphorylation, (final common pathway for aerobic metabolism), may be altered. Clinically can appear like episodes besides to progressive muscle weakness. Differential diagnosis is based on clinical history, including detailed search for history of exposure to drugs, that might have adverse effects similar to muscle metabolic disorders. Molecular diagnosis allows establishing definitive diagnosis, as well as to perform genetic counseling and to provide a personalized treatment, now or in the future.

An aPPARent Functional Consequence in Skeletal Muscle Physiology via Peroxisome Proliferator-Activated Receptors.

Skeletal muscle comprises 30–40% of the total body mass and plays a central role in energy homeostasis in the body. The deregulation of energy homeostasis is a common underlying characteristic of metabolic syndrome. Over the past decades, peroxisome proliferator-activated receptors (PPARs) have been shown to play critical regulatory roles in skeletal muscle. The three family members of PPAR have overlapping roles that contribute to the myriad of processes in skeletal muscle. This review aims to provide an overview of the functions of different PPAR members in energy homeostasis as well as during skeletal muscle metabolic disorders, with a particular focus on human and relevant mouse model studies.

What is MR spectroscopy?

1H-Magnetic Resonance Spectroscopy (MRS) is a novel advanced imaging technique used as an adjunct to MRI to reveal complementary non-invasive information about the biochemical composition of imaged tissue. Clinical uses...

Metabolic muscle disorders in infants and children

Metabolic myopathies refer to a group of heterogeneous hereditary muscle disorders associated with known enzymatic defects. These conditions affect the ability of muscle fibers to maintain adequate energy and adenosine triphosphate (ATP) concentrations. Conventionally these diseases are grouped into abnormalities of lipid, glycogen, purine or mitochondrial me- tabolism. This review will focus on current diagnosis and management of pediatric patients presenting with a suspected meta- bolic myopathy.

MicroRNA-149 inhibits PARP-2 and promotes mitochondrial biogenesis via SIRT-1/PGC-1α network in skeletal muscle.

High-fat diet (HFD) plays a central role in the initiation of mitochondrial dysfunction that significantly contributes to skeletal muscle metabolic disorders in obesity. However, the mechanism by which HFD weakens skeletal muscle metabolism by altering mitochondrial function and biogenesis is unknown. Given the emerging roles of microRNAs (miRNAs) in the regulation of skeletal muscle metabolism, we sought to determine whether activation of a specific miRNA pathway would rescue the HFD-induced mitochondrial dysfunction via the sirtuin-1 (SIRT-1)/ peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, a pathway that governs genes necessary for mitochondrial function. We here report that miR-149 strongly controls SIRT-1 expression and activity. Interestingly, miR-149 inhibits poly(ADP-ribose) polymerase-2 (PARP-2) and so increased cellular NAD(+) levels and SIRT-1 activity that subsequently increases mitochondrial function and biogenesis via PGC-1α activation. In addition, skeletal muscles from HFD-fed obese mice exhibit low levels of miR-149 and high levels of PARP-2, and they show reduced mitochondrial function and biogenesis due to a decreased activation of the SIRT-1/PGC-1α pathway, suggesting that mitochondrial dysfunction in the skeletal muscle of obese mice may be because of, at least in part, miR-149 dysregulation. Overall, miR-149 may be therapeutically useful for treating HFD-induced skeletal muscle metabolic disorders in such pathophysiological conditions as obesity and type 2 diabetes.

Muscle Disease

On the basis of strong research evidence, Duchenne muscular dystrophy (DMD), the most common severe childhood form of muscular dystrophy, is an X-linked recessive disorder caused by out-of-frame mutations of the dystrophin gene. Thus, it is classified asa dystrophinopathy. The disease onset is before age 5 years. Patients with DMD present with progressive symmetrical limb-girdle muscle weakness and become wheelchair dependent after age 12 years. (2)(3). On the basis of some research evidence,cardiomyopathy and congestive heart failure are usually seen in the late teens in patients with DMD. Progressive scoliosis and respiratory in sufficiency often develop once wheelchair dependency occurs. Respiratory failure and cardiomyopathy are common causes of death, and few survive beyond the third decade of life. (2)(3)(4)(5)(6)(7). On the basis of some research evidence, prednisone at 0.75 mg/kg daily (maximum dose, 40 mg/d) or deflazacort at 0.9 mg/kg daily (maximum dose, 39 mg/d), a derivative of prednisolone (not available in the United States), as a single morning dose is recommended for DMD patients older than 5 years, which may prolong independent walking from a few months to 2 years. (2)(3)(16)(17). Based on some research evidence, treatment with angiotensin-converting enzyme inhibitors, b-blockers, and diuretics has been reported to be beneficial in DMD patients with cardiac abnormalities. (2)(3)(5)(18). Based on expert opinion, children with muscle weakness and increased serum creatine kinase levels may be associated with either genetic or acquired muscle disorders (Tables 1 and 3). (14)(15)

Future Directions in Malignant Hyperthermia Research and Patient Care

Malignant hyperthermia (MH) is a complex pharmacogenetic disorder of muscle metabolism. To more closely examine the complexities of MH and other related muscle disorders, the Malignant Hyperthermia Association of the United States (MHAUS) recently sponsored a scientific conference at which an interdisciplinary group of experts gathered to share new information and ideas. In this Special Article, we highlight key concepts and theories presented at the conference along with exciting new trends and challenges in MH research and patient care.

179th ENMC international workshop: Pregnancy in women with neuromuscular disorders: 5–7 November 2010, Naarden, The Netherlands

Sixteen doctors and scientists met in Naarden, The Netherlands, from 5 to 7 November 2010 to review current knowledge in the field of pregnancy in women with neuromuscular disease. The group was joined by three patients and their families. Participants were from eight countries, namely Belgium, Finland, France, Germany, Italy, Norway, The Netherlands and the United Kingdom. A variety of disciplines were represented, including neurology, clinical genetics, cardiology, respiratory medicine, obstetrics and gynaecology, epidemiology, ethics, a nurse specialist, and a representative from the ENMC research committee. Parenthood is a highly desirable aim in life for many couples, and increasingly this also applies to women affected by neuromuscular disorders (NMDs). Little is known about the effect of individual NMD on the course of pregnancy and delivery and conversely the effect of pregnancy on muscles themselves [1]. In the past, many patients have been discouraged from undertaking pregnancy for a variety of reasons. The overarching aim of the workshop was to harness knowledge about pregnancy in NMD with the intention of improving maternal and fetal outcomes. The workshop was structured to first review existing knowledge in the field, and second to propose practical recommendations for each stage of pregnancy, both in general terms and also specific to individual or groups of conditions, for use by all

Recurrence quantification analysis of sustained sub-maximal grip contractions in patients with various metabolic muscle disorders

Recurrence quantification analysis (RQA) was used to analyse force signals during sustained sub-maximal grip contraction (SSGC) of three types of patients suffering from a metabolic muscle disorder (glycogen storage disease type III (GSD III), glycogen storage disease type V (GSD V) and mitochondrial myopathies (MITO)) compared to control subjects. Recurrence plots (RP) of patients showed clear non-uniformity, in comparison to control subjects who displayed quasi-periodic patterns. Quantitative analysis of the RP showed significant differences between patients with metabolic disorders and the control group for four RQA parameters. The results showed that the SSGC signals of patients had decreased L max, which indicated more chaotic patterns. In addition the deterministic component of the signals was less complex for patients than for controls. The differences of SSGC signal observed using RP and RQA were possibly related to the underlying changes in metabolism of muscle fibres due to the disease. Results of this study illustrate that the RQA technique is well suited to analyse sustained grip-force signals.

Myoadenylate deaminase deficiency: clinico-pathological and molecular study of a series of 27 Spanish cases

Myoadenylate deaminase deficiency (MADD) is the most common metabolic muscle disorder. Here we report the largest study to date of MADD in Spanish patients, including clinical, histological, and molecular data. Most of the patients presented with moderate clinical symptoms of exercise intolerance, including myalgia, fatigability and cramps. In 70% of the patients, serum creatine kinase (CK) was elevated. Muscle biopsy showed mild, nonspecific alterations with absent histochemical reaction for MAD. Eight cases ofMADD were coincidental with other associated diseases, and had more severe tissue alterations upon muscle biopsy. The mutation C34T in the MAD gene was present in a homozygous state in 26 of the 27 patients. One patient was a compound heterozygote for the C34T/G468T mutations. We conclude that MADD should be suspected in patients with exercise intolerance and with idiopathic hyperCKemia. Since symptoms may be subtle, we recommend routine histochemical analysis of MAD in all muscle biopsies, followed by molecular analysis in MAD-negative cases.

Insulinorésistance et insuffisance rénale chronique

Insulin resistance is characterized by a lesser biological response to a standard level of insulin. Currently the most popular method used to quantify insulin resistance is the homeostasis model of assessment of insulin resistance (HOMA-IR). A state of insulin resistance is present from the early stages of chronic renal failure (CRF). Defects in glucose utilization observed during CRF concern both nonoxidative metabolism (storage in the form of glycogen) and oxidative metabolism. Resistance to the action of insulin during the CRF concerns traditionally peripheral tissues, particularly skeletal muscle. The mechanisms are multiple: retention of nitrogenous waste, metabolic acidosis, hypovitaminosis D or inflammation. The insulin resistance is associated with a disturbance of endothelial function and is involved in increased vascular risk and aggravates muscle metabolic disorders. Recent studies demonstrated a link between insulin resistance and progression of renal failure. Physical activity is known to improve insulin resistance status, the correction of metabolic abnormalities and attempts to reduce the inflammatory syndrome are potential targets of treatment. Thiazolidinedione have recently shown their interest, but in CRF the balance between risk and benefit remains to be evaluated.

Metabolic Syndrome Predicts Frailty

SAN FRANCISCO — Elderly individuals who have metabolic syndrome are about twice as likely to become frail as those who are healthy, Dr. Joshua I. Barzilay reported in a poster presentation at the Third World Congress on Insulin Resistance Syndrome. The study involved 2,376 individuals aged 69–74 who were followed prospectively for 7–9 years. At baseline none of the participants were frail, nor did they have other illnesses that increase inflammation markers or mimic frailty, reported Dr. Barzilay, of Emory University, Atlanta, and his colleagues. A participant was considered frail if he or she met at least three of the following five criteria: unintentional weight loss of 10 pounds or more in the previous year, low grip strength, self-reported exhaustion, slowness in walking, and low exercise tolerance. A participant was considered “prefrail” if he or she met one or two of the criteria. At the end of follow-up, 169 participants qualified as frail and another 1,082 qualified as prefrail. The three most commonly seen components of frailty were diminished walking speed, diminished strength, and diminished activity, all of which are consistent with sarcopenia. Participants who developed frailty or prefrailty had significantly higher fasting insulin levels, higher white blood cell counts, higher C-reactive protein levels, and higher factor VII levels than those who didn't develop frailty. These participants were 30%–100% more likely to have metabolic syndrome at baseline, compared with those who did not develop frailty or prefrailty. The most common components of the metabolic syndrome in this cohort were increased girth and increased homeostatic model assessment scores. They were also significantly more likely to have developed diabetes at follow-up. In view of the fact that frailty was defined mostly by sarcopenia, the investigators wrote, insulin resistance, inflammation, and frailty are all related to a primary disorder of muscle metabolism.

Exercise tolerance and daily life in McArdle's disease

McArdle's disease is a common disorder of muscle metabolism and is due to myophosphorylase deficiency. The major complaint of patients with this disease is effort intolerance. Although the clinical features of affected patients are well known, their daily lifestyle is not well documented. The main objective of this work was to assess their mean daily energy expenditure (DEE) and compare it with control subjects. Thirty patients and 87 control subjects completed a questionnaire. A 3-day self-record of daily physical activities was used to estimate the mean DEE for patients and control subjects. A separate section of the questionnaire was used to assess patients' clinical features and daily lifestyle. The DEE of patients (44.1 +/- 6.9 kcal/kg) was not significantly different from control subjects (44.5 +/- 5.6 kcal/kg). Half of the patients with McArdle's disease performed a daily physical leisure activity as sport, sometimes at a high level (17%). Despite large individual variation, physical abilities and patients' symptoms were negatively correlated. Physical leisure activity significantly decreased the sensation of muscle pain (P < 0.03). These findings show that patients with McArdle's disease do not have a strictly sedentary lifestyle. Moreover, physical exercise appears to have positive effects on the main clinical features, such as effort intolerance. Thus, regular, moderate physical activity may be beneficial in McArdle's disease.

Metabolic and drug-induced muscle disorders.

The inherited disorders of muscle metabolism affect both substrate utilization and the final intramitochondrial oxidation through the Krebs cycle and the respiratory chain. Almost every step of these complex biochemical pathways can be affected by inborn errors, whose expression depends on peculiar tissue-specific or systemic gene expression. This review updates current knowledge in this broad field. New inherited defects are still being discovered, such as the beta-enolase deficiency in glycogenosis type XIII and mutations in the gene encoding an esterase/lipase/thioesterase protein in Chanarin-Dorfman syndrome, a multisystem triglyceride storage disease. Therapeutic approaches to the metabolic myopathies are still lagging behind, although remarkable observations have been made on the rare coenzyme Q10 deficiency syndrome. However, transgenic animal models may offer the opportunity both to investigate muscle pathogenesis and explore therapeutic targets. Finally, human myotoxicity may provide novel paradigms for naturally occurring muscle disorders.