CARNITINE DEFICIENCY
CASE
A teenage boy was brought to a hospital as he complaints that he used to get too tired when asked to participate in the marching team. The doctor found muscle weakness in the boy’s arms and legs. From the muscle biopsy, the lab pathologist found greatly elevated amount of triglycerides esterified with primary long chain fatty acid. They also fund significant presence of lipid vacuoles in the muscle biopsy.What causes these symptoms?
WHAT IS CARNITINE
• Carnitineis a substance found in almost every cell in the body, it is biosynthesized from the amino acids lysine and methionine. The compound plays a crucial role in energy production, as it is responsible for transporting fatty acids to the mitochondria.
• Carnitinetransports long-chain fatty acids into mitochondria where they are burned (oxidized) to produce energy.
• Carnitinealso transports waste and toxic compounds out of the mitochondria, preventing their buildup. Given these key functions, skeletal and cardiac muscle that use fatty acids as a dietary fuel have high concentrations of carnitine.
• There are three different forms of carnitine:
• L-carnitine
• acetyl-L-carnitine
• propionyl-L-carnitin
ROLE OF CARNITINE
Athletic performance -Someathletestakecarnitinetoimproveperformance -However, twenty years of research finds no consistent evidence that carnitinesupplementscanimproveexerciseorphysicalperformance -Carnitine supplements do not appear to increase the body's use of oxygen or improve metabolic status when exercising, nor do they necessarilyincreasetheamountofcarnitineinmuscl
Aging -A decline in mitochondrial function is thought to contribute to the aging process. Carnitine may be involved because its concentration in tissues declines with age and thereby reduces the integrity of the mitochondrial membrane -Acetyl-l-carnitine may improve mental function and reduce deterioration in older adults with mild cognitive impairment and alzheimer's disease
AFFECTED DISEASE
Cardiovascular and peripheral arterial disease -Management of cardiac ischemia (restriction of blood flow to the heart) and peripheral arterial disease (whose most important symptom is poor circulationinthelegs,knownasintermittentclaudication).
Cancer -Carnitine treat or gave energy to fatigue resulting from chemotherapy, radiation treatment, and poor nutritional status is common in cancer patients Male infertility -The carnitine content of seminal fluid is directly related to sperm count and motility suggesting that the compound might be of value in treating male infertility
HOW MUCH MUCH CARITINE SHOULD YOU CONSUME ?
• It is not necessary for healthy adults and children to take supplements containing carnitineas the liver and kidneys usually produce enough of it.
• In 1989, The Food and Nutrition Board (FNB) of the National Academies (formerly National Academy of Sciences) concluded that carnitineis not an essential nutrient.
• However, people who lack this compound may need to take supplements or eat carnitine-‐enriched foods.
• Foods that provide carnitineare mainly animal products. Red meat has one of the highest concentrations.
• Foods high in carnitineinclude:
• Beef steak, cooked, 4 ounces: 56-‐162 mg
• Milk, 1 cup: 8 mg
• Chicken breast, cooked, 4 ounces: 3-‐5 mg
• Cheese, cheddar, 2 ounces: 2mg
• Adults whose diets are rich in red meat consume on average around 60-‐180 mg of carnitineper day, compared to only 10-‐12 mg per day among vegans.
• The body normally produces enough carnitine. However, some people cannot produce enough of the compound due to genetic or medical reasons.
• According to the Muscular Dystrophy Association2, carnitinedeficiency can be caused by "a genetic mutation in the protein responsible for bringing carnitineinto the cell (primary carnitinedeficiency), or it may occur secondary to other metabolic diseases (secondary carnitinedeficiency)."
When can a carnitine deficiency occur?
• Two types of carnitinedeficiency states exist.
• Primary carnitinedeficiency
•Is a genetic disorder of the cellular carnitine-‐transporter system that usually manifests itself by five years of age with symptoms of cardiomyopathy, skeletal-‐muscle weakness, and hypoglycemia.
•Secondary carnitinedeficiencies
•may occur due to certain disorders (such as chronic renal failure) or under particular conditions (e.g., use of certain antibiotics) that reduce carnitineabsorption or increase its excretion . There is scientific agreement on carnitine'svalue as a prescription product for treating such deficiencies.
• Carnitinehas been studied extensively because it is important to energy production and is a well-‐tolerated and generally safe therapeutic agent .
• Researchers prefer to use acetyl-‐L-‐carnitine in research studies because it is better absorbed from the small intestine than L-‐carnitine and more efficiently crosses the blood-‐brain barrier (i.e., gets into brain tissue) .
Function of Carnitine
• carnitine transports long-‐chain fatty acids into mitochondria where they are burned (oxidized) to produce energy.
• Carnitine transports long-‐chain acyl groups from fatty acids into the mitochondrial matrix
• broken down through β-‐oxidation to acetyl CoA to obtain usable energy via the citric acid cycle
• This reaction is catalyzed by the enzyme fatty acyl-‐CoA synthetase
• The acyl group on CoA can now be transferred to carnitine and the resulting acylcarnitine transported into the mitochondrial matrix.
[2] This occurs via a series of similar steps:
• Acyl CoA is transferred to the hydroxyl group of carnitine by carnitine acyltransferase I (palmitoyltransferase) located on the outer mitochondrial membrane
• Acylcarnitine is shuttled inside by a carnitine-‐acylcarnitine translocase
• Acylcarnitine is converted to acyl CoA by carnitine acyltransferase II (palmitoyltransferase) located on the inner mitochondrial membrane. The liberated carnitine returns to the cytosol.
A teenage boy was brought to a hospital as he complaints that he used to get too tired when asked to participate in the marching team. The doctor found muscle weakness in the boy’s arms and legs. From the muscle biopsy, the lab pathologist found greatly elevated amount of triglycerides esterified with primary long chain fatty acid. They also fund significant presence of lipid vacuoles in the muscle biopsy.What causes these symptoms?
WHAT IS CARNITINE
• Carnitineis a substance found in almost every cell in the body, it is biosynthesized from the amino acids lysine and methionine. The compound plays a crucial role in energy production, as it is responsible for transporting fatty acids to the mitochondria.
• Carnitinetransports long-chain fatty acids into mitochondria where they are burned (oxidized) to produce energy.
• Carnitinealso transports waste and toxic compounds out of the mitochondria, preventing their buildup. Given these key functions, skeletal and cardiac muscle that use fatty acids as a dietary fuel have high concentrations of carnitine.
• There are three different forms of carnitine:
• L-carnitine
• acetyl-L-carnitine
• propionyl-L-carnitin
ROLE OF CARNITINE
Athletic performance -Someathletestakecarnitinetoimproveperformance -However, twenty years of research finds no consistent evidence that carnitinesupplementscanimproveexerciseorphysicalperformance -Carnitine supplements do not appear to increase the body's use of oxygen or improve metabolic status when exercising, nor do they necessarilyincreasetheamountofcarnitineinmuscl
Aging -A decline in mitochondrial function is thought to contribute to the aging process. Carnitine may be involved because its concentration in tissues declines with age and thereby reduces the integrity of the mitochondrial membrane -Acetyl-l-carnitine may improve mental function and reduce deterioration in older adults with mild cognitive impairment and alzheimer's disease
AFFECTED DISEASE
Cardiovascular and peripheral arterial disease -Management of cardiac ischemia (restriction of blood flow to the heart) and peripheral arterial disease (whose most important symptom is poor circulationinthelegs,knownasintermittentclaudication).
Cancer -Carnitine treat or gave energy to fatigue resulting from chemotherapy, radiation treatment, and poor nutritional status is common in cancer patients Male infertility -The carnitine content of seminal fluid is directly related to sperm count and motility suggesting that the compound might be of value in treating male infertility
HOW MUCH MUCH CARITINE SHOULD YOU CONSUME ?
• It is not necessary for healthy adults and children to take supplements containing carnitineas the liver and kidneys usually produce enough of it.
• In 1989, The Food and Nutrition Board (FNB) of the National Academies (formerly National Academy of Sciences) concluded that carnitineis not an essential nutrient.
• However, people who lack this compound may need to take supplements or eat carnitine-‐enriched foods.
• Foods that provide carnitineare mainly animal products. Red meat has one of the highest concentrations.
• Foods high in carnitineinclude:
• Beef steak, cooked, 4 ounces: 56-‐162 mg
• Milk, 1 cup: 8 mg
• Chicken breast, cooked, 4 ounces: 3-‐5 mg
• Cheese, cheddar, 2 ounces: 2mg
• Adults whose diets are rich in red meat consume on average around 60-‐180 mg of carnitineper day, compared to only 10-‐12 mg per day among vegans.
• The body normally produces enough carnitine. However, some people cannot produce enough of the compound due to genetic or medical reasons.
• According to the Muscular Dystrophy Association2, carnitinedeficiency can be caused by "a genetic mutation in the protein responsible for bringing carnitineinto the cell (primary carnitinedeficiency), or it may occur secondary to other metabolic diseases (secondary carnitinedeficiency)."
When can a carnitine deficiency occur?
• Two types of carnitinedeficiency states exist.
• Primary carnitinedeficiency
•Is a genetic disorder of the cellular carnitine-‐transporter system that usually manifests itself by five years of age with symptoms of cardiomyopathy, skeletal-‐muscle weakness, and hypoglycemia.
•Secondary carnitinedeficiencies
•may occur due to certain disorders (such as chronic renal failure) or under particular conditions (e.g., use of certain antibiotics) that reduce carnitineabsorption or increase its excretion . There is scientific agreement on carnitine'svalue as a prescription product for treating such deficiencies.
• Carnitinehas been studied extensively because it is important to energy production and is a well-‐tolerated and generally safe therapeutic agent .
• Researchers prefer to use acetyl-‐L-‐carnitine in research studies because it is better absorbed from the small intestine than L-‐carnitine and more efficiently crosses the blood-‐brain barrier (i.e., gets into brain tissue) .
Function of Carnitine
• carnitine transports long-‐chain fatty acids into mitochondria where they are burned (oxidized) to produce energy.
• Carnitine transports long-‐chain acyl groups from fatty acids into the mitochondrial matrix
• broken down through β-‐oxidation to acetyl CoA to obtain usable energy via the citric acid cycle
• This reaction is catalyzed by the enzyme fatty acyl-‐CoA synthetase
• The acyl group on CoA can now be transferred to carnitine and the resulting acylcarnitine transported into the mitochondrial matrix.
[2] This occurs via a series of similar steps:
• Acyl CoA is transferred to the hydroxyl group of carnitine by carnitine acyltransferase I (palmitoyltransferase) located on the outer mitochondrial membrane
• Acylcarnitine is shuttled inside by a carnitine-‐acylcarnitine translocase
• Acylcarnitine is converted to acyl CoA by carnitine acyltransferase II (palmitoyltransferase) located on the inner mitochondrial membrane. The liberated carnitine returns to the cytosol.
How The People Disorder Metabolize Muscle Glycogen Aerobically
• During any physical activity that can be sustained for longer than a few minutes, the consumption of oxygen to drive the oxidation of carbohydrates and fatty acids.
• This process requires a sufficient delivery of oxygen to the active muscle fibers and an adequate fuel supply within the cell to support oxygen consumption. These fuels include carbohydrates (glycogen and glucose) and fatty acids.
• Since the patient body cannot oxidise fats to obtain energy, glycogen acts like a battery backup for the body.
• Glycogen is an important fuel reserve for several reasons
• Moreover, the glucose from glycogen is readily mobilized and is therefore a good source of energy for sudden, strenuous activity.
• Breakdown of glycogen occurs when energy demands are increased.
• We split glycogen with an enzyme called glycogen phosphorylase.
• This uses inorganic phosphate to form G-‐1-‐P and G-‐6-‐P.
• In muscle, these processe ( glycogen degradation) are regulated to meet the energy needs of the muscle itself.
• The glucose 6-‐phosphate derived from the breakdown of glycogen has three fates (Figure 21.3): (1) It is the initial substrate for glycolysis, (2) it can be processed by the pentose phosphate pathway to yield NADPH and ribose derivatives; and (3) it can be converted into free glucose for release into the bloodstream.
• This conversion takes place mainly in the liver.
• During any physical activity that can be sustained for longer than a few minutes, the consumption of oxygen to drive the oxidation of carbohydrates and fatty acids.
• This process requires a sufficient delivery of oxygen to the active muscle fibers and an adequate fuel supply within the cell to support oxygen consumption. These fuels include carbohydrates (glycogen and glucose) and fatty acids.
• Since the patient body cannot oxidise fats to obtain energy, glycogen acts like a battery backup for the body.
• Glycogen is an important fuel reserve for several reasons
• Moreover, the glucose from glycogen is readily mobilized and is therefore a good source of energy for sudden, strenuous activity.
• Breakdown of glycogen occurs when energy demands are increased.
• We split glycogen with an enzyme called glycogen phosphorylase.
• This uses inorganic phosphate to form G-‐1-‐P and G-‐6-‐P.
• In muscle, these processe ( glycogen degradation) are regulated to meet the energy needs of the muscle itself.
• The glucose 6-‐phosphate derived from the breakdown of glycogen has three fates (Figure 21.3): (1) It is the initial substrate for glycolysis, (2) it can be processed by the pentose phosphate pathway to yield NADPH and ribose derivatives; and (3) it can be converted into free glucose for release into the bloodstream.
• This conversion takes place mainly in the liver.
What are inheritance patterns in metabolic diseases of muscle?
•Most of the metabolic diseases of muscle are inherited in an autosomal recessive pattern
•It means that a person needs two defective genes in order to have the disease.
•One copy is inherited from each parent, neither of whom would normally have symptoms.
•Thus, the disease appears to have occurred “out of the blue,” but in reality, both parents may be carriers, silently harboring the genetic mutation (a flaw in the gene).
•Many parents have no idea they’re carriers of a disease until they have a child who has the disease.
•It means that a person needs two defective genes in order to have the disease.
•One copy is inherited from each parent, neither of whom would normally have symptoms.
•Thus, the disease appears to have occurred “out of the blue,” but in reality, both parents may be carriers, silently harboring the genetic mutation (a flaw in the gene).
•Many parents have no idea they’re carriers of a disease until they have a child who has the disease.
what you should do?
ØBetter diagnosis to allow for earlier identification of at-risk individuals and earlier treatment
ØContinued examination of the role of exercise and diet in metabolic diseases;
ØDevelopment of animal models of metabolic diseases, both to improve understanding of the diseases and to test possible treatments;
ØDevelopment of enzyme replacement therapies
ØDevelopment of gene therapies.
ØContinued examination of the role of exercise and diet in metabolic diseases;
ØDevelopment of animal models of metabolic diseases, both to improve understanding of the diseases and to test possible treatments;
ØDevelopment of enzyme replacement therapies
ØDevelopment of gene therapies.