Disuse Associated Muscle Atrophy
Muscle wasting involves muscle loss or atrophy and usually happens gradually. It can occur because of a variety of conditions.
Muscle wasting can affect a person’s strength and ability to perform everyday activities. Loss of muscle mass directly contributes to exercise intolerance and impaired daily activities, which make it a strong determinant of quality of life and mortality.
Skeletal muscle is not just an organ of locomotion but an essential organ of metabolism and survival. Two common but distinct conditions characterised by the loss of skeletal muscle mass are sarcopenia and cachexia.
Sarcopenia is characterised by the slow and progressive loss of muscle mass associated with ageing without any underlying disease or condition. The prevalence of sarcopenia ranges from 15% at 65 years to 50% at 80 years in humans, with normal ageing associated with a 1–2% muscle loss per year beyond 50 years.
Human evidence indicates a ~30% reduction in muscle cross-sectional area and a ~40% decline in muscle strength at 70 years. Additionally, a rapidly expanding ageing population will only exacerbate the health problems associated with sarcopenia, leading to increased hospitalisations and risk for permanent institutionalisation and disability.
This is likely associated with the fact that older individuals generally do not regain all muscle tissue lost during a period of disuse due in part to falls, fractures, and frailty in the elderly.
Cachexia is associated with chronic diseases, most commonly cancer, and other inflammatory conditions such as chronic obstructive pulmonary disease, heart failure (HF), chronic kidney disease, AIDS, and sepsis.
The overall prevalence of cachexia is approximately 1% of the global patient population, which can increase to 50–80% in cancer patients. Indeed, almost 80% of cancer patients suffering from cachexia will die within one year of diagnosis.
Cancer cachexia is a complex, multifactorial syndrome characterised by a progressive loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and is associated with significant functional impairments.
Cachexia can manifest early in the disease, with ~85% of gastrointestinal and pancreatic cancer patients. It is also evident in up to 80% of patients across a wide range of cancers. Cachexia reduces the quality of life, impairs the response to chemo- and radiotherapy and increases mortality, accounting for 20-30% of all cancer-related deaths. The devastating consequences of cancer cachexia highlight why muscle mass is critical for life.
An overview of the potential mechanisms leading to skeletal muscle wasting and weakness with cancer cachexia.
- Cancer cells release tumour-derived products and cytokines that drive an inflammatory response.
- These changes lead to metabolic alterations, including a significant increase in resting energy expenditure (REE)
- They also cause structural alterations, compromising membrane integrity and disrupting the signalling pathways that maintain cellular homeostasis, leading to increased protein degradation and reduced protein synthesis.
- The resulting overall loss of muscle mass and function (cancer cachexia) is exacerbated by a reduced nutrient intake due to anorexia (loss of desire to eat) induced by the pro-inflammatory environment and anti-cancer treatments such as chemo- and radiotherapy.
As the average hospital stay in older patients is 5-13 days, a short period of hospitalisation can induce a substantial decline in skeletal muscle mass and strength.
Experimental models studying muscle disuse have shown a 2-6% decrease in leg muscle mass and an 8-22% decrease in leg strength following as little as 4-7 days of limb immobilisation in young and older subjects.
The incidence of limb muscle weakness depends on the age of the patient population and the duration of hospital stay. In intensive care units (ICU), muscle weakness is present in only 11% of patients treated in the ICU for 24 hours. ICU muscle weakness increases in 24-55% of patients treated in the ICU for 7-10 days. Longer stays in the ICU are associated with an increased incidence of muscle weakness.
Micregen researchers have an extensive track record in the use of animal models that mimic sarcopenia and cachexia, as well as other muscle degenerative conditions. They have published extensively in international peer-reviewed journals reporting on the underlying mechanisms that lead to these debilitating conditions. In addition, they have been at the forefront of developing therapies for AIDS-related muscle loss. Additionally, the research has shown that a Secretomix based approach significantly dampens muscle damage and promotes regeneration.
The principle modes of action of MRG1161 in tissue repair and regeneration in muscle atrophy are through:
Decreased inflammation
Increased angiogenesis
Regulation of protein catabolism and anabolism
Reduced mitochondrial dysfunction
Activation of resident stem cell and tissue-specific progenitor cell populations
Beneficial remodelling of the extracellular matrix
Anti-apoptotic and chemotactic signalling
Protection of myocytes from oxidative stress.
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