Lack of regular physical activity (Hypokinesis)
Women exercising in the Rancho Bernardo Study were at significantly less risk of sarcopenia than non-exercising women. Walking was the main form of exercise performed by the women.
Resistance training improves the balance of protein within the muscle, allowing more muscle protein synthesis than breakdown of the contractile elements. The result is muscle maintenance or even hypertrophy. Chronic resistance training increases both muscle protein synthesis and breakdown, but synthesis at a greater magnitude. This positive protein balance restores protein in those who have lost mass and prevents muscle mass loss in those who are not already sarcopenic. In addition protein-building satellite cells, which aid in muscle repair and hypertrophy, increase in proportion in response to training. Exercise also stimulates protein synthesis by enhancing insulin sensitivity; thus contributing to the positive protein balance.
A lack of physical activity, especially resistance training, results in a negative protein balance in which protein breakdown occurs at a faster rate than protein synthesis. If more protein is destroyed than manufactured in the muscle, muscle wasting occurs.
One can be predisposed to sarcopenia by having low muscle mass before old age. The more lean muscle mass one has to begin with, the more one can afford to lose before becoming sarcopenic.
Change in Muscle Protein Metabolism
Factors affecting muscle protein metabolism:
±Insulin-like growth factor (IGF-1)
±Inflammatory agents (cortisol and cytokines)
±Growth hormone and other hormones
* + symbol represents an increase or decrease
Any one of these factors, if increased or decreased may disrupt the building and breakdown of proteins. In sarcopenia, those factors aiding in degradation may increase proportionally or those inhibiting degradation may decrease proportionally to the other factors affecting protein breakdown. The same may occur with protein synthesis. A decrease in synthesizers or increase in synthesis inhibitors will also lead to muscle wasting.
Myosin Heavy Chain (MHC) protein is the main protein under scrutiny in current research. MHC is one of the components which aids in cross-bridge formation with actin in muscle contraction. The production of MHC is reduced as much as 44% in the elderly.
↓GH (growth hormone)
↑Leptin with increased fat mass
↑Insulin resistance with inactivity
↑Cortisol, TNF, IL-6
The anterior pituitary gland produces less growth hormone (GH) with advancing age. GH stimulates the liver to produce insulin-like growth factor 1 (IGF-1), which stimulates muscle protein synthesis. Local IGF-1 in the tissue is stimulated by GH as well as testosterone, and may be important for stimulating muscle growth as well as repair. GH and leptin, a cytokine secreted by fat cells, show an inverse relationship in concentration. This finding indicates that less GH is secreted in an individual with more adiposity. Thus, sarcopenia in the obese may be exacerbated by a more severe decline in GH levels.
Decreased testosterone occurs in both genders and may coincide with an increased circulating concentration of leptin in males. Testosterone is an anabolic hormone responsible for the 40% additional muscle mass that men have over women in the young adult years.
Menopause greatly reduces the estrogen production in women; however current research indicates that post menopausal women with hormone replacement have the same prevalence of sarcopenia as those without hormone replacement. Additionally, estrogen is a more powerful aid in fat deposition than protein synthesis.
Myostatin is a factor which inhibits differentiation of myoblasts into muscle cells, preventing hyperplasia (creation of new muscle cells). Cross sectional research supports an inverse relationship between serum myostatin levels and lean body mass (muscle).
Leptin is a cytokine, or inflammatory agent, associated with fat cells. It counteracts the blood sugar modifying effects of insulin, as well as the release of GH. Leptin is produced in greater quantities in obese individuals, accentuating sarcopenia in the obese as the fat mass conceals declining lean body mass.
With age and obesity, insulin sensitivity often decreases. Insulin has some anabolic properties, however, its most important role is in the regulation of glucose and its relation to type II diabetes. Refer to the Diabetes section of this website for more information.
Cortisol and IL-6 are released into the bloodstream as part of an inflammatory response. Levels of these agents change in sarcopenia, cortisol increasing along with IL-6 and no reduction in TNF (tumor necrosis factor) and IL-1 (anti-inflammatory agent). Causes of inflammation can be varied from arthritis to diabetes.
The neuromuscular junction, the communication site between the nerve and muscle cell, is reduced in size with increasing age and inactivity. There is a reduction in the number of receptors for acetylcholine, the neurotransmitter which sends the nerve’s message to the muscle cells; this weakens the end plate potential. Acetylcholine’s message instructing the muscle cell to contract will be weaker. This creates a greater chance of the message not meeting the threshold level of stimulus to allow the muscle sarcolemma (cell membrane) to depolarize and initiate contraction.
The number and velocity of alpha motor neurons (neurons which connect to the muscle at the neuromuscular junction) decrease with age and may contribute to sarcopenia. Motor units grow larger as the functioning alpha motor neurons attempt to reinnervate cells which have lost their neural input. This process causes loss of fine motor control and atrophy of the muscle cells receiving no neural input. Ultimately, loss of muscle tissue and strength will result with this neuromuscular decline.
DNA Deletion Theory
- DNA is not only held in the nuclei of cells, but in the mitochondria (organelle in the cell which turns food into useable energy) as well.
- Cutting edge research is investigating deletion mutations, which “chop up DNA,” of the mitochondrial DNA.
- Oxidative stress (from high LDL cholesterol, smoking, diabetes, etc) is the proposed culprit causing the deletion.
- The DNA which is partially deleted is then replicated faster than healthy DNA because it is smaller.
- As more of the deletion-containing genomes predominate, the energy production of the mitochondria will decline, specifically by dysfunction of the electron transport chain which leads to more oxidative stress in the cell.
- This dysfunction stimulates the nuclear DNA to trigger the production of more mitochondria. However, the deletion mitochondrial DNA will predominate in the new mitochondria because of its smaller size.
- With the increase in diseased mitochondria, energy deficiency and oxidative stress will increase until the muscle fiber (cell) atrophies and eventually breaks.
- If this happens on a large scale, whole muscles can be subject to the significant atrophy common to sarcopenia.
Apoptosis means “programmed cell death.” Apoptosis can be initiated by excess calcium in the cytosol (cell fluid), physiologically produced oxidants, TNF, and other agents. Current investigation into the role of oxidants produced by mitochondria with deletions in the DNA is of great interest to scientists. The oxidative damage brought about by faulty mitochondria may initiate the sequence of factor release which carries on apoptosis. Apoptosis can dramatically reduce muscle fibers, and thus contribute to the cause of sarcopenia.
Anorexia is common in the elderly. This condition is linked with early satiation due to a less adaptive fundus of the stomach, increased release of CCK (released in response to a fatty meal, an excess will cause the fullness feeling earlier in a meal and cause loss of appetite) hormonal changes such as increased leptin, depression, cytokine release, and other factors. Inadequate protein and amino acid intake can severely disrupt the protein synthesis necessary to maintain protein balance and muscle mass.Reference (34)
More on Anorexia and the elderly: [link]