Sarcopenia and Aging of Muscle - AGHE meeting in San Jose, Feb. 2001
                                Notes by Augustine G. DiGiovanna
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Background –

    Muscle mass begins to decrease at approx. age 30, and the rate of decrease becomes much faster at approx. age 50. Most muscle mass loss is in the lower body rather than the upper body musculature. The age-related decrease in muscle mass is linear in XS studies after age 50. Problems and contradictions develop when comparing different means for measuring muscle mass (e.g. lean body weight, potassium content, creatinine clearance, dual energy x-ray absorptiometry, CAT scans, tissue biopsies, protein content, protein synthesis rates, etc., etc. Loss of muscle mass may be undetected if only body weight is measured because there is often a simultaneous decrease in muscle mass with and increase in on-muscle body mass (e.g., body fat).

Significance of decreased muscle mass -

    Significant loss of muscle mass (i.e., sarcopenia) seems to be positively associated with age-related  declines in physical abilities and with increases in physical disabilities. Some evidence suggests a correlation between sarcopenia and incidence, types, and degrees of decline in physical abilities (e.g., IADLs, balance, falls).

    Though it is suspected and believed that sarcopenia contributes to decline in physical ability and to disability and physical limitations, the quantitative relationships between sarcopenia and physical ability have not been studied. There may be an association between muscle mass and mortality rate or mortality risk.

    Muscle strength may be a more important parameter than muscle mass in determining the adverse effects of age-related muscle decrements and age-related declines in physical abilities. Muscle strength is a more important parameter than is muscle mass in determining the effectiveness of muscles in performing ordinary tasks (e.g., standing up from a sitting position). There are no clear data on the effects of sarcopenia on ML or on mortality rates or on amount of disability or quality of life.

    Evidence suggests that hand grip strength is positively associated with lower mortality rate. This association is much stronger than any association between body mass index (BMI) and mortality rate.

    Muscle strength may have an average decline of 15% per decade at ages 50-60 and 30% per decade after age 60.

    Muscle "quality" involves mass, strength, speed, control, endurance, control, task-specific performance, and perhaps other parameters.

Definition of significant loss of muscle mass (sarcopenia) -

    There is no standard definition for sarcopenia. One definition is having a lean body mass less than two standard deviation below the mean for normal young adults.

Incidence or sarcopenia –

    Incidence of sarcopenia may be approx. 20% or higher for elderly men and 30% or higher for elderly women.

Possible causes of sarcopenia -

    1.      genetic factors

    2.      altered circulation

    a.    decrease in circulation

    b.   decrease in the capillary:muscle fiber ratio

    3.      changes in the nervous system

    a.   altered motor neurons

    b.   denervation

    c.    deterioration of motor end plates

    d.   selective reinnervation of Type I fibers

    4.      inflammatory responses causing muscle damage

    5.      reduced exercise

    6.      malnutrition

    a.    low dietary protein intake

    b.  Vitamin D deficiency or age-related decline in vitamin D

    7.      oxidative stress (free radicals and other ROS)

    8.      muscle mitochondrial mutations (i.e., mtDNA deletions)

    a.    mtDNA mutations, especially in Type II fibers, which have greater age-related atrophy and loss than Type I fibers

    9.      changes in specific types of muscle fibers

    a.    selective loss of Types II fibers

    b.   selective atrophy of Type II fibers (perhaps the major factor)

    c.    conversion of Type II fibers to Type I fibers

    d.   Though the rate of LOSS of Type I and Type II fibers may be the same, there is a faster age-related ATROPHY of Type II fibers, leading to a disproportionate loss of muscle mass and muscle strength from decline in Type II muscle mass. The Type II fibers have type II myosin (the Type I fibers have type I myosin heavy chains). Age-related declines in muscle strength and muscle speed may be affected largely by age-related atrophy of Type II fibers and, especially, in age-related decline in type II myosin. Age-related decline in type II myosin is important because the type II myosin form the contractile cross-bridges AND because the type II myosin is the ATPase that supplies the energy for contraction.

    10.  decline in muscle protein

    a.    decline in muscle protein synthesis with no age-related change in degradation rates of muscle protein. 

    b.   decline in specific muscle proteins (e.g., MHC, mitochondrial, SR).

    c.    dysregulation of hormones controlling muscle protein synthesis

    1.      anabolic hormones and factors

    (a)   sex steroids (e.g., menopause)

    (b)   GH

    (c)   insulin-like growth factor I (IGF-I), which is the "active" messenger from GH.

    (d)   DHEA

    2.      catabolic hormones and factors

    (a)   glucocorticoids, which cause decreased muscle mass by causing increased muscle protein breakdown

    (b)   stress or therapies that increase glucocorticoids

    (c)   catabolic cytokines (e.g., IL-6, tumor necrosis factor alpha{TNF)

    (d)   mystatin

    (e)   thyroid hormones

    (f)     insulin

    11.  Diseases

    a.       any disabling disease

    1.      strokes

    2.      Alzheimer’s disease

    3.      Parkinson’s disease

    4.      osteoporsis

    b.      any disease causing malnutrition

    c.       atherosclerosis

    d.      diabetes mellitus

    1.      hyperinsulimemia

    e.       renal failure

    f.        hypogonadism

    g.       etc.


  Possible treatments for sarcopenia -

     There is a need to establish treatments for sarcopenia. The causes, mechanisms, and treatments for sarcopenia are just beginning to be explored.

      1.      exercise

    a.    The benefits in increased muscle mass and strength from exercise may be the same as those with exercise plus GH supplements. However, the GH supplements may also cause adverse side effects (e.g., carpal tunnel syndrome, diabetes). Therefore, to increase muscle mass and strength, exercise seems better then exercise plus GH secretion stimulators.

    b.   Exercise in elders improves many skeletal muscle parameters including mass, strength, power, speed, control, and endurance. Some of the effect may be from stimulation of myosin heave chain protein (MHC).

    c.    Different exercise regimens cause different degrees of hypertrophy in Type I muscle fibers more than Type II muscle fibers. Some evidence shows that resistance training produces more hypertrophy in Type I fibers than in Type II fibers.

    d.   electrical stimulation of muscles during disability or inability to exercise.

 

    2.      dietary modification

    a.    Sarcopenia may be reduced by adequate protein intake (approx. 1.25 gm per day per kg body weight.

    b.   AA supplements can stimulate muscle protein synthesis and, thus, may help reduce sarcopenia.

    1.      An increase in amino acid intake may stimulate muscle protein synthesis, especially after exercise. Part of the reason may be the increase in blood flow through muscles due to the exercise. Timing of the increase in amino acid intake seems to be important. Increases in amino acids seem to increase muscle protein synthesis most when the AAs arrive immediately after the exercise rather than at some hours later. (i.e., AAs increase muscle protein synthesis best when they enter the blood stream immediately after exercise rather than some hours later.

    c.    timing of dietary protein intake relative to time of exercise.

 

    3.      hormone supplementation (e.g., testosterone, GH, IFG-I, DHEA)

    a.   testosterone

    1.      different forms of testosterone may have different levels of activities and different sites of activities.

    2.      measurement of body levels of testosterone are difficult because of the different forms of testosterone (e.g., bound, free).

    3.      The degree of effects from testosterone supplementation may be different in frail elderly men that in normal elderly men. These include both the potential benefits and the potential side effects. Therefore, the effects of testosterone supplementation must be MUCH more extensively researched before testosterone supplementation is recommended for testosterone-normal elderly men.

    4.      The effects, pathways, side effects, and outcomes in terms of mass, strength endurance, power, etc. from anabolic steroid supplementation on muscle are not clear. There may be different types of testosterone forms that can be designed to "hit" specific receptors or have more specialized effects, just as "designer" estrogens can do. This is an area of important future research. Right now, unless there is a clearly indicated testosterone deficiency, it is best to avoid using testosterone supplements to augment the muscle system.

    b.   GH and IGF-I

    1.      The relationship between age-related declines in GH, in IGF-I, in testosterone, and in DHEA are not known. Nor are the potential adverse effects from supplementation with these hormones in :normal" individuals.


Free radical, oxidation, and muscle –

     There is an age-related increase in membrane lipid peroxides and oxidized muscle proteins, including those in the sarcoplasmic reticulum and in mitochondria. FRs also damage mtDNA. (Point mutations in mtDNA come from maternal inheritance of mitochondria, while most mtDNA deletions occur in somatic cells rather than being inherited.) Some mtDNA deletions occur at much higher frequencies than do other mtDNA deletions.

 

    The age-related accumulation of types and numbers of mtDNA deletions may derive from FR damage. Any cause of increased oxidative stress may promote increased mtDNA deletions in muscle tissues and in other tissues.

  sources of FR damage to mtDNA

1.  ordinary mitochondrial activities

2.  very strenuous exercise

3.  non-mitochondrial diseases (e.g., cirrhosis, chronic renal failure).

 

    mtDNA is more susceptible to oxidative damage than is nuclear DNA because mtDNA has no protein coating and because mtDNA is closer to the sources of oxidative damage from mitochondria. Also, cells use a higher proportion of mtDNA than of nuclear DNA, so mutations in mtDNA have a greater chance of having and effect and of having a more significant effect compared to mutations in nuclear DNA.

 

    mtDNA deletions include 4977, 7326, and 10422. There is an age-related increase in these deletions. There is an age-related increase in both the number of types of mtDNA deletions and in the absolute number of mtDNA deletions.

 

    A single muscle cells can have mitochondria with different mtDNA mutations, a condition called "heteroplasmy." Heteroplasmy occurs with greater frequency in muscle tissue than in other tissues studied. Muscle cell mtDNA heteroplasmy increases with age.

    

    One muscle cell can have more than one region of mtDNA mutant mitochondria. Some muscle cells show much more heteroplasmy than other neighboring muscle cells. Heteroplasmy of mtDNA in muscle cells shows little overlap or mixing of mtDNA. This shows clonal distribution (perhaps clonal replication) of the mtDNA mutant mitochondria. This is called "segmental" distribution of mutant mtDNA mitochondria.

 

    Through clonal selection during mitochondrial replications, the COX mutant damaged mitochondria produce at a more rapid rate (mitochondria with  other types of damage outside their mtDNA are selected against), causing the muscle cell to accumulate many COX mtDNA mitochondria. The mechanisms selecting for COX mutant mitochondria is not known. Therefore, accumulation of mtDNA mutants does not depend upon a vicious cycle of FR damage to mtDNA, but to a natural selection of mtDNA mutant mitochondria.


Effects from mtDNA deletion mutations -

     In a muscle cells, a mitochondrion with an mtDNA mutation causing damage to the cytochrome oxidase enzyme in the electron transport system produces less energy but more FRs.

 

    Since the COX  mutant mitochondria cannot produce energy efficiently, they produce many FRs. These FRs may cause damage to cells throughout the body (e.g., atherosclerosis).

 

    There was more COX mutation in Type II fibers than in Type I fibers in this study. Other studies showed more COX- mutations in Type I fibers. The mtDNA mutations studied were COX- for cytochrome oxidase or SDH + for excess succinate dehydrogenase.

 

    Muscle cells with mutant mtDNA are thinner (atrophied) relative to normal mtDNA regions.

 

    Since the COX protein is coded by mtDNA, this shows mtDNA mutations. Since the SDH enzyme is coded for by nuclear DNA, the presence of extra SDH in portions of muscle cells (i.e., segmental distribution of SDH),  suggests that the cell nucleus responds to mitochondrial damage (perhaps declining energy production) by synthesizing extra SDH and having the extra SDH moved to the mtDNA mutant areas of the muscle cells.


Effects from damaged mitochondria - Sarcopenia

    Mitochondrial damage and abnormalities may lead to sarcopenia, cell injury and cell death through several mechanisms including (a) decline in ATP production (b) mitochondrial signaling proteins (e.g., apoptosis-inhibiting factor), and  (c) calcium ion regulation.

 

    Type II fibers have fewer mitochondria than do Type I fibers normally. Therefore, mtDNA mutations in Type II fibers can have more effect on the fiber since it has fewer normal mitochondria to begin with. mtDNA mutations that damage muscel fibers, especially Type II fibers, can contribute to sarcopenia. The preferential atrophy of Type II fibers with aging may be due, in part, to the preferential presence of mtDNA mutants in Type II fibers together with the normally lower number of mitochondria in Type II fibers to begin with.

 

    A hypothesis that contradicts the "vicious cycle" hypotheses is the "reductive hotspot" hypothesis. This hypothesis (RHH) states that mitochondrial FRs that escape from mitoch. send their oxidative potential out of the cell through reactions at the cell membrane, producing extracellular SO (superoxide) FRs. These SO FRs cause extracellular damage to lipids, which in turn, cause FR damage to other cell membranes including lysosomes. Damaged lysosomes then cause cell injury. Thus, FR production in a few muscle cells or a few muscle cell mitochondria can spread their damaging capabilities and effects to any other cells in the body. Since this mechanisms includes some reduction reactions as well as oxidative reactions outside the cells, the name includes the term "reductive".


Reducing FR damage in muscle (and elsewhere) -

    There seems to be an age-related decline in the ability of proper exercise to increase certain antioxidant defense mechanisms in skeletal muscle.

 

    Vitamin E and vitamin C supplements MAY increase the antioxidant effects of exercise, but the effect is only suggested by a small amount of research. More research is needed.

 

    Caloric restriction (CR) reduces the development of oxidative damage in muscle mitochondria. However, short term CR cannot reverse previously incurred mitochondrial oxidative damage in AL animal muscle.


Glycation -

    Glycation within muscle cells or other cells has not been well studied. There is a little research showing that glycation and glycoxidation of ATPases in muscle cell. The non-enzymatic glycation of muscle ATPase and other intracellular muscle proteins is catalyzed by metal ions (e.g., Cu, Fe), which are present in the cell. Intracellular antioxidants help prevent glycoxidation of muscle cell ATPase. The possibility of glycoxidation of myosin or actin has not been studied yet.


Hyperinsulinemia and aging muscles –

    Insulin, especially hyperinsulinemia, may have adverse age-related effects through several mechanisms. These may include

       promoting FR damage to proteins

1.  increasing H2O2

2.  increasing NO

3.  increasing NO-caused mitochondrial damage.

4.  lipid peroxidation, especially in mitochondrial membrane lipids, by increasing the amount of polyunsaturated lipids. These lipids are more susceptible to FR damage. (This mechanisms may also be a way that hyperinsulinemia promotes atherosclerosis by promoting lipid peroxidation in arteries.)

       decreasing removal of damaged proteins

1.  decreased proteosome activity. This may lead to adverse effects from insulin by accumulation of damaged proteins.

 

    The two types of transporters for glucose into muscle cells are GLUT-I and GLUT 4. GLUT-I does not respond to insulin. Insulin and exercise increase the activity of GLUT-4 by stimulating its movement from intracellular storage areas to the sarcolemma. Insulin also stimulates the actions of GLUT-4. Type I fibers have more GLUT-4 than do Type II fibers.

 

    The age-related decline in GLUT-4 seems to be from decreased exercise, not decreased effects of insulin.

 

    Exercise increases GLUT-4 preferential in Type II fibers. Therefore, the age-related decline in insulin sensitivity and in GLUT- 4 transporters and in glucose clearance may be due in large part to lack of exercise Effects include

1.       decline in number of Type II fibers

2.       atrophy of remaining Type II fibers

3.       decreases in GLUT-4 transporters on the remaining Types II fibers.

Caloric restriction (CR) may work, in part, by reducing insulin levels, thus reducing the age-related adverse effects from insulin and hyperinsulinemia.


Age-related changes in muscle proteins -

    The three kinds of MHC are MHCI, MCHIIA, and MHCIIx. MHCI is in Type I fibers, MHCIIA and MHCIIb are in Type II fibers.

 

    There are age-related declines in MCHI and in MCHIIa. There is an age-related decline in MHC synthesis rates.

 

    The age-related decline in MCH synthesis rate seems to be greater than the age-related decline in actin protein synthesis rate in muscle. This includes synthesis rates before and immediately after exercise.

 

    FR damage to muscle proteins is specific. Only certain types of FR damage occur. Some types of FR damage to muscle protein is not age-related, and other types are age-related. Therefore, to determine age-related effects of FR damage on muscle proteins, the right types of proteins and the right AAs in the proteins must be analyzed.

 

    Damaged proteins are removed intracellularly by structures called "proteosomes". Proteosomes have a complex mechanisms for identifying abnormal or unwanted proteins and destroying them. The by-products of this protein degradation can be recycled to make other proteins or other cell components. By removing damaged proteins, proteosomes can protect against age-related adverse changes. Inhibition of proteosomes leads to more cell damage and to programmed cell death.

 

    Androgen steroids can stimulate muscle protein synthesis.  The mechanisms is unknown. The mechanisms may include altering gene activity in muscle cells directly, increasing IGF-I or by inhibiting the catabolic effects of glucocorticoids.

 

    There seems to be no age-related change in the enzyme that recharges ADP from creatine phosphate (i.e., creatine phosphate kinase).


Voluntary control of muscle actions -

    Steadiness of muscle contraction shows an age-related decline., The decline is probably due to neurologic, neuromuscular, and muscular age-related changes.

 

    Part of the age-related decline in muscle control may be due to an age-related decline in muscle control when other mental tasks are being performed simultaneously

 

    Elders may use strategies and muscle contraction sequences different from those used by young adults to obtain the same motor action. These differences may be compensatory, not pathological or detrimental.

 

    A study  of the human thyroarytenoid muscle. - Contrary to somite-derived skeletal muscle, at least some visceral arch-derived skeletal muscle has a higher age-related decline in Type I fibers than in Type II fibers. The loss of Type I fibers is accompanied by hypertrophy of the remaining Type I fibers.

 

    Skeletal muscle in the laryngeal region seems to undergo age-related changes that are different in kind, in degree, and in direction to the age-related changes observed in other skeletal muscle. This difference may be due to the different embryological origin of laryngotracheal skeletal muscle, which is from the visceral arches rather than from the myotome of somites. For example, there may be some muscle cell regeneration in laryngotracheal muscle throughout life.

 

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   © Copyright 2001 - Augustine G. DiGiovanna - All rights reserved.
This material MAY be reproduced or distributed in any form or by any means, or stored in any data base or retrieval system ONLY under one of the following two conditions: (1) If no individual, group, organization, institution, company, corporation or other entity is charged for its use and only for use by instructors and students in courses where students are required to purchase the book HUMAN AGING: BIOLOGICAL PERSPECTIVES by Augustine G. DiGiovanna, The McGraw-Hill Companies, New York, 1994 or 2000; (2) If prior written permission is obtained from Augustine G. DiGiovanna.