Sarcopenia, the age-related loss of muscle mass and strength, has many possible contributing causes. There is fair evidence for most of them, from a failure to process amino acids needed for construction of new muscle mass to damaged neuromuscular junctions to loss of stem cell function. The most compelling evidence I've seem points to that stem cell dysfunction as the most significant contribution. It is certainly the case that stem cell populations decline in size and activity with age, reducing the supply of daughter cells needed to maintain tissues in good condition. Muscle stem cells are among the most studied in aging research.
The paper noted here picks through the major themes in sarcopenia, and makes the argument for linking at least some of them to age-related issues in mitochondrial function. The mitochondria are the power plants of the cell, and muscle is an energy-hungry tissue. Mitochondria can suffer forms of damage that make them harmful to their cells and the surrounding tissue; this is a significant issue in aging. More generally, all mitochondria change for the worse in old tissues, possibly in reaction to other forms of molecular damage characteristic to old tissues. They alter in shape and dynamics, and their ability to generate the energy store molecules required for cellular operations declines. How much of sarcopenia can be explained by these phenomena? Some, I think, possibly not all.
Using a targeted metabolomics approach, participants with low muscle quality presented significantly higher plasma concentrations of isoleucine and leucine, suggesting that low muscle quality is characterized by impaired transport of amino acids, especially branched chain amino acids (BCAAs), across the muscle cell membrane. The exact reasons for why amino acid uptake is reduced in older persons with low muscle quality are unknown, and further work is required to identify putative intervention/therapeutic targets.
Physiologically, amino acid uptake in muscle cells is regulated by three fundamental mechanisms: insulin signalling, BCAA (primarily leucine) blood concentration, and physical activity. Previous studies have also suggested that these 'anabolic' signals cause increased amino acid entry by dynamically enhancing muscle perfusion, and all three signals exhibit a dose-response relationship that is steeper in younger than in older persons. In other words, older persons tend to develop an 'anabolic resistance' to the three stimuli. Since muscle perfusion adaptation is mediated by endothelial reactivity, which is hampered by a pro-inflammatory state, this hypothesis can also explain why inflammation is such a strong correlate and predictor of age-related sarcopenia.
During ageing, mitochondria lose the ability to produce energy during maximal efforts but not when the energetic demand is lower. This impaired mitochondrial function could be due to inadequate perfusion or reduced muscle blood flow, resulting in lower oxygen delivery in skeletal muscle and diminished aerobic capacity. This hypothesis is interesting because it connects both energetic and anabolic deficits to the same mechanism. These results indicate that oxidative phosphorylation is progressively impaired with ageing; it is unclear whether this is because the number of mitochondria per muscle volume is diminished, the intrinsic capacity of mitochondria to generate ATP is impaired, or the availability of oxygen and nutrients at different levels of effort is compromised.
Oxidative stress and defective mitophagy (mitochondrial autophagy) are potentially involved in the decline of muscle quality with ageing and need to be considered. Dysfunctional mitochondria are characterized by reduced oxidative phosphorylation efficiency and excessive production of reactive oxygen species, which oxidize and damage macromolecules. The hypothesis that oxidative stress causes degenerative changes in tissues that are highly metabolically active, such as the brain and the muscle, has been proposed for many years. Oxidative stress may also affect satellite cells or muscle stem cell pools in skeletal muscle.
Defective mitochondrial function has been studied in regard to the neuromuscular junction (NMJ) remodelling that occurs with ageing, producing cycles of denervation-innervation that lead to motor unit loss, specifically in type II fibres, as well as muscle fibre atrophy. However, it is not clear whether these changes in the NMJ precede or follow the observed decline in muscle mass and strength that is observed with ageing. Some studies have reported altered mitochondria morphology in the NMJ that produce increased levels of oxidative stress, decreased enzymatic activity and ATP production, and impaired calcium buffering. The combination of these biological changes may have a strong negative impact on excitation-contraction coupling and eventually lead to the loss of motor units.
Overall, low muscle quality seems to be associated with (i) metabolic impairments that lead to reduced incorporation of the three major BCAAs, which are used by muscle as energy sources and are associated with muscle strength and endurance; (ii) fat accumulation in muscle tissue that ultimately leads to architectural disruption and loss of function; and (iii) high concentration of lipid species that are associated with impaired mitochondrial function and unrecycled mitochondrial proteins, potentially due to defective mitophagy or proteostasis. The extent and complexity to which these mechanisms are interconnected is unknown and should be examined in future studies. In addition, other factors that impact ageing muscle could also modulate mitochondrial function, such as (i) defects in the NMJ that leads to myofiber denervation-due to reduced capacity in motor neurons to reinnervate muscle fibres-consequently causing fibres to become atrophied; (ii) the age-associated decline in the satellite cell pool, reducing muscle regeneration after injury; and (iii) 'inflammaging', the chronic low-grade inflammation observed in older persons.