Sarcopenia is the name given to loss of muscle mass and strength that occurs with age. When it comes to assembling evidence for causes of the condition, this is one of the better examples of the present state of understanding in aging. A sizable number of potential causes have convincing evidence, all may be relevant, but the degree to which they are important relative to one another is hard to discern. Further, the layering of the causative mechanisms, how they interact, and whether and to what degree some are secondary to others, is also hard to discern. The only truly reliable method of answering such questions is to fix just one contributing cause, and observe the results. The field of biotechnology is on the verge of being able to achieve that goal for sarcopenia and a number of other age-related conditions, but not quite there yet.
What is the usual approach given the inability to fix a cause of age-related disease in isolation? Make it worse instead. The research community can break cellular biochemistry in ways that exaggerate certain manifestations of aging - such as the oxidative stress under examination in today's open access paper. It is, however, very challenging to say whether or not such a study produces results that are useful or actionable. Forms and amounts of damage that do not occur in normal aging produce results that might superficially resemble aspects of aging, might tell us something, or might be completely irrelevant to our understanding of aging. The details matter, and they are wildly different in every case, and sometimes the research community simply doesn't have a good enough understanding of the specific mechanisms to be able to mount a good argument as to whether or not the study is useful.
Among the candidates for contributing causes of sarcopenia are chronic inflammation, loss of stem cell activity, dysregulation of dietary protein processing necessary for tissue growth, decline of nerve-muscle junctions, and reduced density of capillary networks and thus a reduction in nutrient supply to tissues. There are others. The paper here looks at rising levels of oxidative stress, increased amounts of reactive oxidizing molecules generated by cells and roaming throughout tissues; these molecules cause damage that must be repaired, but more importantly trigger all sorts of cellular reactions that, collectively, don't help the situation. This is an aspect of aging that goes hand in hand with chronic inflammation, and is secondary to deeper causes that include mitochondrial dysfunction and cellular senescence.
Sarcopenia, the age-related loss of muscle mass and strength, is a major cause of morbidity and mortality in the elderly population. While muscle atrophy contributes to weakness, the decline in muscle strength is more rapid than the atrophy, suggesting a deficit in intrinsic force-generating properties of the muscle. The age-related muscle weakness independent of loss of mass is defined as dynapenia and involves the excitation-contraction coupling machinery of the muscle fibres. A progressive increase in cellular oxidative stress during ageing has been implicated as a major contributor to sarcopenia.
Excitation-contraction coupling involves a sequence of events whereby action potential-driven excitation of the sarcolemma results in rapid changes in cytoplasmic calcium concentration leading to activation of force-generating machinery in the sarcomere. In mammalian skeletal muscle, this process may dictate the rates of relaxation and a termination of a variety of Ca2+-dependent signalling pathways and gene transcription events that influence muscle quality and quantity. These processes imply the critical importance of calcium handling in the muscle fibre as dysregulation of calcium homoeostasis has been associated with reduced specific force in ageing and conditions of increased oxidative stress.
Our lab has previously used a mouse model of oxidative stress that was created by deleting cellular antioxidant enzyme Cu/Zn superoxide dismutase (Sod1-/-) resulting in many features of rapid and accelerated sarcopenia. The reduction in specific force in these mice is only partially rescued via direct muscle stimulation that bypasses the neuromuscular junction, suggesting a loss of functional innervation in these mice but also defects within fibres. Moreover, interrogation of the function of single permeabilized fibres showed no difference between Sod1-/- and wild-type (WT) mice indicating no impairment in the Sod1-/- mice in the inherent function of the contractile machinery and suggests that there may be declines in the functioning of the excitation contraction machinery.
The goal of this study was to determine whether the loss of innervation and the chronic increase in cellular oxidative stress in the Sod1-/- mice affect the excitation-contraction apparatus in a manner similar to muscles of old WT mice. We report that the disruption of excitation-contraction coupling contributes to impaired force generation in the mouse model of Sod1 deficiency. Briefly, we found a significant reduction in sarcoplasmic reticulum Ca2+ ATPase (SERCA) activity as well as reduced expression of proteins involved in calcium release and force generation. Another potential factor involved in EC uncoupling in Sod1-/- mice is oxidative damage to proteins involved in the contractile response.
In summary, this study provides strong support for the coupling between increased oxidative stress and disruption of cellular excitation contraction machinery in mouse skeletal muscle. The novel quantitative mechanistic data provided here can lead to potential therapeutic interventions of SERCA dysfunction for sarcopenia and muscle diseases.