Sarcopenia and Aging of Muscle - AGHE meeting in San Jose, Feb. 2001

                                Outline by Augustine G. DiGiovanna
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Muscle mass

    1.    begins to decrease at approx. age 30

    2.    rate of decrease becomes much faster at age 50

    3.    decrease in muscle mass is linear after age 50

    4.    most muscle mass loss is in the lower body rather than the upper body

    5.    problems and contradictions with techniques for measuring muscle mass

    6.    loss of muscle mass may be undetected if only body weight is measured

POSSIBLE significance

    1.      lower physical abilities (e.g., IADLs, balance, falls)

    a.       incidence

    b.      types

    c.       degrees
2.    temperature regulation (less muscle to make heat and to reduce heat loss)
3.    medication dosages and timing (altered lean body mass, metabolic rate, and water distribution)

    2.      physical disabilities

    3.      mean longevity

    4.      mortality risk

    5.      quality of life

            (e.g., pleasure, recreation, social, economic, psychological, cosmetic, self-efficacy, independence, self-determination, morale

    6.      relationships not studied

    7.      muscle mass VS. muscle strength

    a.       possible negative correlation between hand grip strength and mortality rate

    b.      stronger correlation than between body mass index (BMI) and mortality rate

    8.      muscle mass VS. speed, control, endurance, task-specific performance

    9.      average rates of decline in strength

    a.       15% per decade at ages 50-60

    b.      30% per decade after age 60

    c. average total ;loss of 50% or more by age 70

DEFINITION of significant loss of muscle mass = sarcopenia

    1.      no standard definition for sarcopenia

    a.       lean body mass  <  2 SD below mean for normal young adult

Incidence or sarcopenia –

    1.      > 20% for elderly men

    2.      > 30%  for elderly women

     3.    > 50% in some population

Possible causes of sarcopenia -

    1.      genetic factors

    2.      altered circulation

    3.      changes in the nervous system

    4.      inflammatory responses causing muscle damage

    5.      reduced exercise

    6.      malnutrition

    7.      oxidative stress (free radicals and other ROS)

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

    a.    especially in Type II fibers

    9.      changes in specific types of muscle fibers

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

    b.   selective loss of Types II fibers

    c.    conversion of Type II fibers to Type I fibers

    10.  decline in muscle protein

    a.    decline in muscle protein synthesis 

    b.   decline in certain proteins (e.g., MHC, SR, mitochondria).

    c.    dysregulation of hormones (e.g., decreased lvels of testosterone, GH, IGF-I, DHEA, estrogen in women: higher levels of glucocorticoids, cytomine like IL-^, tumor necrosis factor alpha thyroid hormones, insulin)

    1.      anabolic hormones and factors

    2.      catabolic hormones and factors

    11.  Diseases

    a.       any disabling disease

    b.      any disease causing malnutrition

    c.       atherosclerosis

    d.      diabetes mellitus

    1.      hyperinsulinemia

    e.       renal failure

    f.        hypogonadism

    g.       etc.

POSSIBLE treatments for sarcopenia

    1.      exercise

    a.    can improve mass, strength, power, speed, control, and endurance

    b.   different exercise regimens cause different effects

    c.    can affect cells preferentially (Type I, Type II)

    d.   electrical stimulation

    2.      dietary modification

    a.    protein intake (1.25 gm per day per kg body)

    b.   amino acid supplements

    c.    timing of  protein intake

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

    a.   testosterone

    1.      different forms

    2.      difficulty in measuring levels

    3.      different forms

    4.      unknown effects (“designer” hormones)

    (a)    pathways

    (b)   side effects

    (c)    mass

    (d)   strength

    (e)    endurance

    (f)     power

    (g)    normal VS. frail elders

    5.      need MUCH more research

    b.   GH, IGF-I, DHEA

    1.      “unknown territory”

Free radical, oxidation, and muscle –

    1.      age-related increases in -

    a.       membrane lipid peroxides

    b.      oxidized muscle proteins

    c.       oxidized sarcoplasmic reticulum proteins affecting calcium reabsorption

    d.      mitochondria

    e.       damaged mtDNA

    f.        mtDNA deletions

    2.      sources of FR damage to mtDNA

    a.       ordinary mitochondrial activities

    b.      very strenuous exercise

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

    3.      mtDNA sensitivity to FR damage

a.      no protein coating

b.      closer to the sources of oxidative damage

c.      use higher proportion of mtDNA

    4.      age-related increase in muscle mtDNA deletions

    a.       number

    b.      types

    5.      mtDNA heteroplasmy

    a.       high frequency in muscle tissue

    b.      increases with age.

    c.       more than one region per cell

    d.      variable amounts among cells

    e.       clonal distribution (perhaps clonal replication)

    1.      natural selection for mtDNA deletion mitochondria

    f.        not a vicious cycle of FR damage to mtDNA

Effects from mtDNA deletion mutations -

    1.      less energy output (e.g., mutation in COX {cytochrome oxidase)

    2.      more FR production

    a.       may stimulate nuclear antioxidant genes

    3.      damage to cells throughout body (e.g., atherosclerosis).

    4.      may affect Type I or Type II preferentially

    5.      atrophy (may be regional from heteroplasmy)

Effects from damaged mitochondria

    1.      decline in ATP production

    2.      mitochondrial signaling proteins (e.g., apoptosis-inhibiting factor)

    3.      calcium ion regulation

    4.      sarcopenia (preferential for Type II fibers)

    5.      "reductive hotspot" hypothesis

            a. leads to damage in other body cells

            b. damages lysoomes leading to vcell injury and cell death

            c. promotes athrosclerosis

Reducing FR damage in muscle (and elsewhere) -

    1.      exercise (depends upon types, amounts, etc.)

            a. less effeectiveness with increasing age

    2.      antioxidant supplements ??

    a.       Vitamin E

    b.    Vitamin C
3. caloric restriction (CR) (reduces FR damage and reduces insulin levels)

Glycation (intracellular)

      1.      little research

    a.       glycoxidation of ATPase

    b.      catalyzed by metal ions (e.g., Cu, Fe)

    c.       intracellular antioxidants may limit intracellular glycoxsidation

    d.      myosin or actin ??

Hyperinsulinemia and aging muscles –

    1.      possible effects

    a.       promoting FR damage to proteins

    _1.        increasing H₂O₂

    2.      increasing NO

    3.      increasing NO-caused mitochondrial damage.

    4.      increasing lipid peroxidation (e.g., mitochondrial membranes)

    b.      decreasing removal of damaged proteins

    1.      decreased proteosome activity

    2.      exercise leads to increased GLUT-4 transporters

    3.      caloric restriction leads to lower insulin levels

Age-related changes in muscle proteins-

    1.      types or myosin heavy chains (MHCs)

    a.       MHCI in Type I fibers

    b.      MHCIIA and MHCIIb in Type II fibers.

    2.      age-related declines in MHC synthesis

    3.      FR damage and proteosomes

    4.      effects from androgens 

Voluntary control of muscle actions

    1.      steadiness

    2.      strategies

    3.      thyroarytenoid muscle and laryngotracheal muscle are different

            a. different patterns of muscle fiber atrophy and loss, ability to regenerate, etc.

            b. may be due to difference in embryological origin from visceral arches, not somite myotome)

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