In older men, ten days of bed rest preserved mitochondrial energy capacity but reduced organelle count and sharply increased resting free radical output
In older men, ten days of bed rest preserved mitochondrial energy capacity but reduced organelle count and sharply increased resting free radical output
Researchers placed ten healthy men over 65 on ten days of strict bed rest and biopsied the quadriceps muscle before and after. Mitochondrial capacity to produce energy remained unchanged both at rest and at maximal stimulation. Yet organelle number declined, and resting production of reactive oxygen species, the toxic byproducts of energy metabolism, surged.
Short bed rest damages the body more than intuition suggests. In a classic 1960s experiment, three weeks of immobility reduced peak oxygen consumption (the central measure of aerobic fitness) in young men more severely than the next thirty years of normal life. The ten-day period examined in this new study was chosen deliberately: it matches the typical hospital stay or home recovery for an older person after illness. In the ten participants (men averaging 68.5 years of age), quadriceps volume fell by 6.2%, muscle thickness by 7.4%, and strength by 13.3%.
The paper was published on September 11 in the Journal of Physiology, one of the world's oldest physiology journals, founded in 1878. The researchers expected mitochondrial function to decline first, since mitochondria are the energy-producing organelles of the muscle cell. Instead, muscle fiber respiration, measured at rest, under stimulation with adenosine diphosphate (ADP, the substrate for synthesizing ATP, the cell's primary fuel), and at maximal capacity, showed no change on any parameter. Protein levels within the respiratory complexes were likewise unchanged.
What did change was visible under the electron microscope. The researchers manually traced more than 11,500 individual mitochondria in muscle fibers before and after the experiment. The fraction of cell area occupied by mitochondria decreased: there were physically fewer organelles. The remaining mitochondria worked harder per unit of their own mass, compensating for the loss in number with greater per-organelle efficiency.
At the same time, production of reactive oxygen species, which are harmful to the cell in excess, increased, but only at rest. When the researchers added ADP to simulate muscle work, the excess production stopped.
Gene sequencing of the muscle tissue revealed altered activity in more than 3,000 genes. Genes responsible for building new mitochondria were suppressed, while genes involved in clearing damaged organelles became active. Yet the proteins needed to complete this clearance did not increase: the dismantling of old mitochondria starts but is not carried through. Antioxidant defenses were also disrupted. The scavenger enzyme GPX1 was suppressed, while the gene NRF2, the cell's master emergency regulator of antioxidant defense, was sharply upregulated. In human cells, a similar decision point between mitochondrial repair and dismantling involves the MGRN1 checkpoint.
The same laboratory had previously tested an identical ten-day protocol in young adults. In those subjects, the marker of mitochondrial quantity did not decline over the same period. The difference is specifically attributable to age.
The authors conclude that the reduction in peak oxygen consumption observed in older people after short hospitalization is more likely explained by the cardiovascular and microvascular systems that deliver oxygen to the muscle, since mitochondrial respiration itself withstood ten days of disuse. This shifts the target for prevention: beyond muscle, which exercise protects, older adults recovering from injuries and hospitalizations need to safeguard the vasculature delivering oxygen to the muscle and the cell's antioxidant defenses, which deteriorate within just ten days of immobility. In older women, a comparable period of limb immobilization disrupts the dialogue between muscle stem cells and connective tissue.