HNH37506, Metabolic consequences of muscle wasting (HNH37506)
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Metabolic consequences of
chronic diseases lecture notes
Introduction to cancer cachexia
For the development of cachexia, cytokines and lipid molecules play a
role. In cachexia, the tumour is silenced from the inflammatory state,
but the rest of the body is activated in an inflammatory state. Because
of the inflammatory state, muscle breakdown can occur. A couple of
cancer types really contribute to cancer cachexia and these are listed
below:
Most of the times, cancer cachexia is related to cancer types in the
digestive system. Lung cancer can result in the switch of type 1 fiber to
type 2 fiber, which can result in fatigue from breathing. The same switch is seen in COPD patients.
Cancer cachexia: a multifactorial syndrome characterized by ongoing loss of muscle mass (with or
without loss of fat mass) that cannot be fully reversed by nutritional support and leads to progressive
functional impairment. The pathophysiology is characterised by a negative protein and energy
balance driven by a variable combination of reduced food intake and abnormal metabolism.
Sarcopenia (muscle loss) is associated with postoperative infection and delayed recovery from cancer
surgery. Sarcopenia is also related to early dose-limiting toxicities, thus, low doses of drugs can
already give a lot of side-effects. Weight loss is related to the different stages of cancer treatment:
chemotherapy, surgery, palliative care phase etc. During the entire treatment, chronic intervention
occurs to preserve body weight by implementing a specific diet and physical activity. In case of acute
,weight loss, acute interventions occur to preserve body weight. This includes patient tailored
counselling and, for example, parental nutrition.
The relation between fat mass and muscle mass is important for
cancer survival. Survival rate is lowered when the muscle mass is less
(or especially in sarcopenic state), BMI is less related to cancer
survival. However, fat infiltration in muscle fibres can result in
decreased muscle contraction and lower function capacity, and thus in
reduced survival. Drug doses are dependent on body volume, more
fat mass needs other dugs doses (shown in the image).
BIA (bioelectrical impedance analysis) together with other scans (for
example CT scans) can give better predictions of the survival of the
patient (disease activity and treatment toxicity). The tests investigate the body composition, cell
membrane integrity and cell function. CT scans can specifically measure fat mass.
Chemotherapy can result in taste disorders, which can affect the dietary behaviour of cancer patients
(they eat less because the food is less tasty). Disease induced anorexia is when patients eat less due
to tumour side-effects, resulting in too little body weight and less survival.
Fasting mimicking diets in mice showed beneficial effects on the shrinkage of tumours, but the
research to this is still ongoing, since tumour-induced anorexia results in a lower survival rate. It could
be that a ketogenic diet results in shrinkage of the tumour.
Palliative care can reduce morbidity and mortality in cancer. Palliative care can improve the quality of
life by relieving cancer related pain. Palliative
care starts when a patient is going to die.
Mortality is improved because the palliative care
results in a longer, healthier life.
In a cancer patient, the brain shows an altered
pattern of hypothalamic mediators, which can
cause loss of appetite, hyposmia (the reduced
ability to smell and taste), and hypogeusia
(diminished sensitivity to taste). The image
shows an overview of cancer effects on several
organ types.
, Early diagnosis of cachexia is important to effectively treat cancer.
Muscle wasting, mechanistic insights
Skeletal muscle has a constant turnover of proteins (build-up and breakdown). Every couple of week
to months, we renew our muscle, making it easy to adapt to certain situations. Multiple causes of
muscle deconditioning (muscle breakdown, weaker muscles) exist:
Sarcopenia
Muscle disuse -> when you don’t use muscle for a certain time (cast), you will lose muscles
Cancer cachexia
COPD
Obesity
Type 2 diabetes
Cardiovascular disease
Critical illness (metabolic stress)
Muscle atrophy: a weakening or reduction of muscle
mass caused either by age, starvation or physical
inactivity. Muscle atrophy due to physical activity is
dependent on time. Muscle atrophy is related to strength
loss (also worsens over time).
Muscle mass is maintained when there is a net protein
balance between breakdown and synthesis. Proteins
related to this net protein balance are myofibrillar,
mitochondrial and sarcoplasmic proteins. Muscle protein
synthesis and
breakdown are also
dependent on the
amount of food you eat. In a fasting state, muscle protein
synthesis goes down and muscle protein breakdown goes up.
This is reversed for the state when you eat food (see image).
Only a small amount of protein synthesis is used for muscle
synthesis, this is shown in the image on the right. Protein
ingestion via diet and physical activity are anabolic stimuli for
protein synthesis. Especially resistance exercise is a good way of overcoming the periods of protein
breakdown (and to get more protein synthesis).
Activating mTORC1 has a direct effect on protein anabolism. mTORC1 can be activated via contractile
activity (resistance exercise) and via amino acids or insulin obtained from food products. The insulin
can also inhibit FOXO1. Due to this, protein degradation is inhibited. mTORC1 is the downstream
signalling pathway for protein synthesis. Some anabolic signals for mTORC1 stimulation are essential
amino acids, dietary proteins, insulin, glucose, the protein source/quality, growth factors, and muscle
contraction.
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