Metabolic myopathies are

myopathies In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease (Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meani ...

that result from defects in biochemical metabolism that primarily affect muscle. They are generally genetic defects that interfere with muscle's ability to create energy. At the cellular level, metabolic myopathies lack some kind of

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that prevent the chemical reactions necessary to create adenosine triphosphate (ATP). ATP is often referred to as the "molecular unit of currency" of intracellular

energy transfer In physics, energy (from Ancient Greek: ἐνέργεια, ''enérgeia'', “activity”) is the quantitative property that is transferred to a body or to a physical system, recognizable in the performance of work and in the form of heat ...

. The lack of ATP prevents the muscle cells from being able to function properly. Some people with a metabolic myopathy never develop symptoms due to the body's ability to produce enough ATP through alternative pathways. ATP → ADP + P_i + energy → muscle contraction ATP is needed for

muscle contraction Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as ...

by two processes: # Firstly, ATP is needed for transport proteins to actively transport

calcium ions Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction of ...

into the

sarcoplasmic reticulum The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other Cell (biology), cells. The main function of the SR is to store calcium ions (Ca2+). Calcium in bio ...

(SR) of the muscle cell between muscle contractions. When a nerve signal is received, calcium channels in the SR open briefly and calcium rushes into the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

by selective diffusion (which does not use ATP). The diffusion of calcium ions into the cytosol causes the myosin strands of the myofibril to become exposed, and the myosin strands pull the actin microfilaments together. The muscle begins to contract. # Secondly, ATP is needed to allow the myosin to release and pull again, so that the muscle can contract further in what is known as the

sliding filament model Sliding may refer to: *Sliding (dance), also floating or gliding, a group of footwork-oriented dance techniques *Slide (baseball), an attempt by a baseball runner to avoid getting tagged out *Sliding (motion) See also *Slide (disambiguation) Sl ...

. ATP is consumed at a high rate by contracting muscles. The need for ATP in muscle cells is illustrated by the phenomenon of

Rigor mortis Rigor mortis (Latin: ''rigor'' "stiffness", and ''mortis'' "of death"), or postmortem rigidity, is the third stage of death. It is one of the recognizable signs of death, characterized by stiffening of the limbs of the corpse caused by chemic ...

, which is the muscle rigidity that occurs in dead bodies for a short time after death. In these muscles, all the ATP has been converted to ADP, and in the absence of further ATP being generated, the calcium transport proteins stop pumping calcium ions into the sarcoplasmic reticulum and the calcium ions gradually leak out. This causes the myosin proteins to grab the actin and pull once but without further supply of ATP, cannot release and pull again. The muscles therefore remain rigid in the position at death until the binding of myosin to actin begins to break down and they become loose again.

Symptoms

In the event more ATP is needed from the affected pathway, the lack of it becomes an issue and symptoms develop. People with a metabolic myopathy often experience symptoms such as: *

exercise intolerance Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe post ...

, * muscle fatigue, pain and cramping during and/or after exercise, * shortness of breath (

dyspnea Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathing, breathe well enough. The American Thoracic Society defines it as "a subjective experience of brea ...

) or rapid breathing (

tachypnea Tachypnea, also spelt tachypnoea, is a respiratory rate greater than normal, resulting in abnormally rapid and shallow breathing. In adult humans at rest, any respiratory rate of 1220 per minute is considered clinically normal, with tachypnea be ...

), * inappropriate rapid heart rate in response to exercise (

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...

), * exaggerated cardiorespiratory (breath and heart rate combined) response to exercise (

and

),Noury, JB., Zagnoli, F., Petit, F. ''et al.'' Exercise efficiency impairment in metabolic myopathies. ''Sci Rep'' 10, 8765 (2020). https://doi.org/10.1038/s41598-020-65770-y * myogenic

hyperuricemia Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7&nbs ...

(exercise-induced accelerated breakdown of purine nucleotides in muscle via

Purine Nucleotide Cycle Purine is a heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines a ...

), * muscle contracture (like a really bad cramp that can last for hours, which is myogenic and EMG silent), * progressive muscle weakness, *

myoglobinuria Myoglobinuria is the presence of myoglobin in the urine, which usually results from rhabdomyolysis or muscle injury. Myoglobin is present in muscle cells as a reserve of oxygen. Signs and symptoms Signs and symptoms of myoglobinuria are usual ...

and considerable breakdown of muscle tissue (

rhabdomyolysis Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of th ...

). The degree of symptoms varies greatly from person to person and is dependent on the severity of enzymatic defect. In extreme cases it can lead to

Rhabdomyolysis Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of th ...

. The symptoms experienced also depend on which metabolic pathway is impaired, as different metabolic pathways produce ATP at different time periods during activity and rest, as well as the type of activity ( anerobic or

aerobic Aerobic means "requiring air," in which "air" usually means oxygen. Aerobic may also refer to * Aerobic exercise, prolonged exercise of moderate intensity * Aerobics, a form of aerobic exercise * Aerobic respiration, the aerobic process of cellu ...

) and its

intensity Intensity may refer to: In colloquial use *Strength (disambiguation) *Amplitude * Level (disambiguation) * Magnitude (disambiguation) In physical sciences Physics *Intensity (physics), power per unit area (W/m2) *Field strength of electric, ma ...

(level of ATP consumption).

Types

Metabolic myopathies are generally caused by an inherited genetic mutation, an

inborn error of metabolism Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrat ...

. (In livestock, acquired GSD is caused by intoxication with the alkaloid

castanospermine Castanospermine is an indolizidine alkaloid first isolated from the seeds of ''Castanospermum australe''. It is a potent inhibitor of some glucosidase enzymes and has antiviral activity ''in vitro'' and in mouse models. The castanospermine deri ...

.) Metabolic myopathies cause the underproduction of adenosine triphosphate (ATP) within the muscle cell. The genetic mutation typically has an autosomal recessive inheritance pattern making it fairly rare to inherit, but it can also be caused by a random genetic mutation. Metabolic myopathies are categorized by the metabolic pathway to which the deficient enzyme belongs. The main categories of metabolic myopathies are listed below: * Muscle

Glycogen Storage Diseases A glycogen storage disease (GSD, also glycogenosis and dextrinosis) is a metabolic disorder caused by an enzyme deficiency affecting glycogen synthesis, glycogen breakdown, or glucose breakdown, typically in muscles and/or liver cells. GSD ha ...

(Muscle GSDs)- defect in sugar (carbohydrate) metabolism. The deficient enzyme occurs in the

of the muscle cell. *

Lipid storage disorder A lipid storage disorder (or lipidosis) is any one of a group of inherited metabolic disorders in which harmful amounts of fats or lipids accumulate in some body cells and tissues. People with these disorders either do not produce enough of one ...

- defect in fat (lipid) metabolism. The deficient enzyme occurs in the cytosol of the muscle cell. * Nucleotide Metabolism disorder- defect in

enzyme (such as AMP deaminase deficiency). Purine nucleotide metabolism is a part of

protein catabolism In molecular biology, protein catabolism is the breakdown of proteins into smaller peptides and ultimately into amino acids. Protein catabolism is a key function of digestion process. Protein catabolism often begins with pepsin, which converts p ...

, and the Purine Nucleotide Cycle occurs within the cytosol of the muscle cell. *

Mitochondrial myopathy Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. On biopsy, the muscle tissue of patients with these diseases usually demonstrate "ragged red" muscle fibers. These ragged-red fibers contain mild accumulation ...

- defect in mitochondrial enzymes for

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...

(including

Citric Acid Cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins ...

and

Electron Transport Chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

). Occurs in the

mitochondrion A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

of the muscle cell.

Diagnosis

The symptoms of a metabolic myopathy can be easily confused with the symptoms of another disease. As genetic sequencing research progresses, a non-invasive neuromuscular panel DNA test can help make a diagnosis. If the DNA test is inconclusive (negative or VUS), then a

muscle biopsy In medicine, a muscle biopsy is a procedure in which a piece of muscle tissue is removed from an organism and examined microscopically. A muscle biopsy can lead to the discovery of problems with the nervous system, connective tissue, vascular sys ...

is necessary for an accurate diagnosis. A

blood test A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a hypodermic needle, or via fingerprick. Multiple tests for specific blood components, such as a glucose test or a cholester ...

for

creatine kinase Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme () expressed by various tissues and cell types. CK catalyses the conversion of creatine and uses adenosine triphosphate (ATP) to create phosp ...

(CK) can be done under normal circumstances to test for signs of tissue breakdown, or with an added cardio portion that can indicate if muscle breakdown is occurring. An electromyography (EMG) is sometimes taken in order to rule out other disorders if the cause of fatigue is unknown. An

Exercise Stress Test A cardiac stress test (also referred to as a cardiac diagnostic test, cardiopulmonary exercise test, or abbreviated CPX test) is a cardiological test that measures the heart's ability to respond to external stress in a controlled clinical environ ...

can be used to determine an inappropriate rapid heart rate (

sinus tachycardia Sinus tachycardia is an elevated sinus rhythm characterized by an increase in the rate of electrical impulses arising from the sinoatrial node. In adults, sinus tachycardia is defined as a heart rate greater than 100 beats per minute (bpm). The ...

) response to exercise, which is seen in GSD-V, other glycogenoses, and mitochondrial myopathies. A 12 Minutes Walk Test (12MWT) can also be used to determine " Second Wind" which is also seen in McArdle Disease (GSD-V). A cardiopulmonary exercise test can measure both heart rate and breathing, to evaluate the oxygen cost (∆V’O₂/∆Work-Rate) during incremental exercise. In both glycogenoses and mitochondrial myopathies, patients displayed an increased oxygen cost during exercise compared to control subjects; and therefore, can perform less work for a given VO₂ consumption during submaximal daily life exercises. Differentiating between different types of metabolic myopathies can be difficult due to the similar symptoms of each type such as

and

. It has to be determined whether the patient has fixed or exercise-induced manifestations; and if exercise-related, what kind of exercise, before extensive exercise-related lab testing is done to determine the underlying cause. Adequate knowledge is required of the body's

bioenergetic systems Bioenergetic systems are metabolic processes that relate to the flow of energy in living organisms. Those processes convert energy into adenosine triphosphate (ATP), which is the form suitable for muscular activity. There are two main forms of syn ...

, including: * which circumstances constitute

anaerobic exercise Anaerobic exercise is a type of exercise that breaks down glucose in the body without using oxygen; ''anaerobic'' means "without oxygen". In practical terms, this means that anaerobic exercise is more intense, but shorter in duration than aerobi ...

(blood flow restricted by contracted muscles, insufficient oxygen and blood borne fuels, particularly

isometric exercise An isometric exercise is a form of exercise involving the static contraction of a muscle without any visible movement in the angle of the joint. The term "isometric" combines the Greek words ''isos'' (equal) and ''-metria'' (measuring), meaning ...

, as well as sudden increased

) versus

aerobic exercise Aerobic exercise (also known as endurance activities, cardio or cardio-respiratory exercise) is physical exercise of low to high intensity that depends primarily on the aerobic energy-generating process. "Aerobic" is defined as "relating to, inv ...

(blood flow unrestricted), *

anaerobic metabolism Anaerobic respiration is respiration using electron acceptors other than molecular oxygen (O2). Although oxygen is not the final electron acceptor, the process still uses a respiratory electron transport chain. In aerobic organisms undergoing re ...

(ATP produced without oxygen, regardless of adequate blood flow or not, quickly produces ATP which is useful in high-intensity activity and the beginning of any activity) versus

aerobic metabolism Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...

(ATP produced with oxygen, adequate blood flow required, slow to produce ATP but produces for longer and high yield), * the different sources of energy ( phosphagen system,

carbohydrate metabolism Carbohydrate metabolism is the whole of the biochemistry, biochemical processes responsible for the metabolic anabolism, formation, catabolism, breakdown, and interconversion of carbohydrates in life, living organisms. Carbohydrates are central t ...

lipid metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In anim ...

ncluding_ketosis.html" ;"title="ketosis.html" ;"title="ncluding ketosis">ncluding ketosis">ketosis.html" ;"title="ncluding ketosis">ncluding ketosis protein metabolism [including the

), * how long does each source take to start producing energy, * how long does each source continue to produce energy, * how long does each source take to replenish, * how much ATP can each source generate, * and which fuel source is primarily used given the intensity of the activity. For example, leisurely-paced walking and fast-paced walking on level ground (no incline) are both aerobic, but fast-paced walking relies on more muscle glycogen because of the higher intensity (which would cause

symptoms in those with muscle Glycogen storage disease, glycogenoses that hadn't yet achieved " Second Wind"). When walking at a leisurely pace on level ground (no incline), but there is loose gravel or sand, long grass, snow, or walking into a headwind, that added resistance (requiring the muscles to tense more) makes the activity more reliant on muscle glycogen also. Those with muscle glycogenoses can maintain a healthy life of exercise by learning activity adaptations, utilizing the bioenergetic systems that are available to them. Depending on the type of activity and whether they are in second wind, they slow their pace or rest briefly when need be, to make sure not to empty their "ATP Reservoir."

Treatment

Metabolic Myopathies have varying levels of symptoms, being most severe when developed during infancy. Those who do not develop a form of a metabolic myopathy until they are in their young adult or adult life tend to have more treatable symptoms that can be helped with a change in diet and exercise. Depending on what enzyme is affected, a high-protein or low-fat diet may be recommended along with mild exercise. It is important for people with metabolic myopathies to consult with their doctors for a treatment plan in order to prevent acute muscle breakdowns while exercising that lead to the release of muscle proteins into the bloodstream that can cause kidney damage. A ketogenic diet has a remarkable effect on CNS-symptoms in PDH-deficiency and has also been tried in complex I deficiency. A ketogenic diet has demonstrated beneficial for McArdle Disease ( GSD-V) as ketones readily convert to Acetyl CoA for oxidative phosphorylation, whereas Free Fatty Acids take a few minutes to convert into Acetyl CoA. As of 2022, another study on a ketogenic diet and McArdle Disease (GSD-V) is underway.

References

External links

Metabolic Myopathies
- eMedicine
IAMGSD
(International Association for Muscle Glycogen Storage Disease)
Walking With McArdle's
- IAMGSD videos
EUROMAC Introduction
- Video about McArdle Disease and the EUROMAC Registry of McArdle Disease and other rare glycogenoses patients Muscular disorders Metabolic disorders {{musculoskeletal-disease-stub