Emergence and Progression of Behavioral Motor Deficits and Skeletal Muscle Atrophy across the Adult Lifespan of the Rat

SIMPLE SUMMARY: Much of what we know about the loss of skeletal muscle strength and mass (sarcopenia) in old age comes from studies of small laboratory rodents. In humans, this condition is generally not noticeable until late middle age when it affects our mobility (clinical stage). As muscle wasting progresses with age, it poses a challenge to independent living and worsens the health of those of us already suffering from other diseases. WHO and national health authorities have identified sarcopenia as one of the major age-related diseases we must try to curb. Observations in humans show that the process underlying sarcopenia goes on for decades before we notice it (preclinical phase). In this study, we show that the same disease process is observed in rats as in humans, and that skeletal muscles exhibit a series of adaptive responses to maintain muscle function and mass during the long period that precedes clinical symptoms. When these adaptive mechanisms are exhausted, the disease progresses to a clinical stage. We conclude that the rat is a useful model to further study the triggering mechanisms of this disease and, moreover, is suitable for assessing whether interventions to treat the disease are more successful in the preclinical phase than in the clinical phase. ABSTRACT: The facultative loss of muscle mass and function during aging (sarcopenia) poses a serious threat to our independence and health. When activities of daily living are impaired (clinical phase), it appears that the processes leading to sarcopenia have been ongoing in humans for decades (preclinical phase). Here, we examined the natural history of sarcopenia in male outbred rats to compare the occurrence of motor behavioral deficits with the degree of muscle wasting and to explore the muscle-associated processes of the preclinical and clinical phases, respectively. Selected metrics were validated in female rats. We used the soleus muscle because of its long duty cycles and its importance in postural control. Results show that gait and coordination remain intact through middle age (40–60% of median lifespan) when muscle mass is largely preserved relative to body weight. However, the muscle shows numerous signs of remodeling with a shift in myofiber-type composition toward type I. As fiber-type prevalence shifted, fiber-type clustering also increased. The number of hybrid fibers, myofibers with central nuclei, and fibers expressing embryonic myosin increased from being barely detectable to a significant number (5–10%) at late middle age. In parallel, TGFβ1, Smad3, FBXO32, and MuRF1 mRNAs increased. In early (25-month-old) and advanced (30-month-old) aging, gait and coordination deteriorate with the progressive loss of muscle mass. In late middle age and early aging due to type II atrophy (>50%) followed by type I atrophy (>50%), the number of myofibers did not correlate with this process. In advanced age, atrophy is accompanied by a decrease in SCs and βCatenin mRNA, whereas several previously upregulated transcripts were downregulated. The re-expression of embryonic myosin in myofibers and the upregulation of mRNAs encoding the γ-subunit of the nicotinic acetylcholine receptor, the neuronal cell adhesion molecule, and myogenin that begins in late middle age suggest that one mechanism driving sarcopenia is the disruption of neuromuscular connectivity. We conclude that sarcopenia in rats, as in humans, has a long preclinical phase in which muscle undergoes extensive remodeling to maintain muscle mass and function. At later time points, these adaptive mechanisms fail, and sarcopenia becomes clinically manifest.