Disuse Associated Muscle Atrophy

Muscle wasting involves muscle loss or atrophy and usually happens gradually. It can occur because of a variety of conditions. As muscle wasting can affect a person's strength and their 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 a loss of skeletal muscle mass are, sarcopenia and cachexia.

Sarcopenia is characterised by the slow and progressive loss of muscle mass that is associated with ageing in the absence of 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 the age of 50 years. Human evidence indicates that a ~30% reduction in muscle cross-sectional area and a ~40% decline in muscle strength are observed at 70 years. Additionally, a rapidly expanding ageing population will only exacerbate the health problems associated with sarcopenia, which directly leads to increased hospitalisations and an increased risk for permanent institutionalisation and disability. This is likely associated with the fact that older individuals generally do not regain all muscle tissue that was lost during a period of disuse, due in part, by contributing to falls, fractures, and frailty in the elderly.

Cachexia is associated not only with chronic diseases, most commonly cancer, but also with 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 cachexia will be dead within 1 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 disease with ~85% of patients with gastrointestinal and pancreatic cancers. It is also evident in up to 80% of patients across a wide range of cancers. Cachexia reduces quality of life, impairs the response to chemo- and radiotherapy and increases mortality, with cachexia accounting for 20-30% of all cancer-related deaths. The devastating consequences of cancer cachexia highlight why muscle mass is critical for life itself.

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 large increase in resting energy expenditure (REE)
  • They also cause structural alterations which compromise membrane integrity and disrupt the signalling pathways involved in the maintenance of cellular homeostasis, leading to an increase in protein degradation and reduction in 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 length of 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 both young and older subjects.

The incidence of limb muscles weakness depends upon the age of the patient population and duration of the hospital stay. In intensive care units (ICU) for example, muscle weakness is present in only 11% of patients treated in the ICU for 24 hours. Whereas the incidence of ICU muscle weakness increases to 24-55% of patients treated in the ICU for 7-10 days. Furthermore, 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 journal reporting on the underlying mechanisms that lead to these devastating conditions. Importantly they have been at the forefront of the context of developing therapies for AIDS related muscle loss. Additionally, the research has shown that a Secretomix based approach has a significant impact in dampening muscle damage and promotes regeneration in acute and chronic models of muscle damage.

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 disfunction
  • 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.