Molecular basis for an attenuated mitochondrial adaptive plasticity in aged skeletal muscle

Abstract

Our intent was to investigate the mechanisms driving the adaptive potential of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria in young (6 mo) and senescent (36 mo) animals in response to a potent stimulus for organelle biogenesis. We employed chronic electrical stimulation (10 Hz, 3 h/day, 7 days) to induce contractile activity of skeletal muscle in 6 and 36 mo F344XBN rats. Subsequent to chronic activity, acute stimulation (1 Hz, 5 min) in situ revealed greater fatigue resistance in both age groups. However, the improvement in endurance was significantly greater in the young, compared to the old animals. Chronic muscle use also augmented SS and IMF mitochondrial volume to a greater extent in young muscle. The molecular basis for the diminished organelle expansion in aged muscle was due, in part, to the collective attenuation of the chronic stimulation-evoked increase in regulatory proteins involved in mediating mitochondrial protein import and biogenesis. Furthermore, adaptations in mitochondrial function were also blunted in old animals. However, chronic contractile activity evoked greater reductions in mitochondrially-mediated proapoptotic signaling in aged muscle. Thus, mitochondrial plasticity is retained in aged animals, however the magnitude of the changes are less compared to young animals due to attenuated molecular processes regulating organelle biogenesis.

Adaptive plasticity of autophagic proteins to denervation in aging skeletal muscle

“…The intent of the present study was to investigate the induction, or lack thereof, of autophagy protein expression in young and aged muscle and to ascertain whether a selective form of autophagy, notably mitophagy, is activated in a similar manner in response to denervation-induced muscle disuse within these two groups. Our data have verified that aged muscle has a reduced ability to adapt to denervation and, thus, possesses a limited range of adaptive plasticity, a property of aged muscle that we previously observed in response to our experimental model of exercise (22). We expanded these conclusions by illustrating that the decreases in autophagy commonly associated with aging (23) may not necessarily be a result of a lack of autophagy gene expression but, rather, a consequence, at least in part, of an attenuated ability to upregulate the autophagy response above an elevated baseline level as an adaptation to muscle disuse.…”

“…However, mitochondria from aged muscle also demonstrated a disruption in cristae structure, and the presence of autophagosomes and lipofuscin is suggestive of impaired mitochondrial degradation. Thus a combination of factors, including fundamental decrements in the transcriptional activation of nuclear genes (22), as well as a possible impairment in the ability of the cell to effectively clear damaged mitochondria, likely led to the reduced mitochondrial content and function in aged muscle.…”

“…This distinctive response is attributable to the multinucleated composition of muscle fibers and the coordinated activation of several catabolic signaling pathways. Although muscle retains its adaptability throughout the life of an organism, tissue malleability is reduced with advancing age (4,22). Aged muscle is further affected by an age-associated loss of skeletal muscle mass and strength, a condition known as sarcopenia (8,22,42).…”

“…Although muscle retains its adaptability throughout the life of an organism, tissue malleability is reduced with advancing age (4,22). Aged muscle is further affected by an age-associated loss of skeletal muscle mass and strength, a condition known as sarcopenia (8,22,42). Although the precise cellular mechanisms responsible for mediating sarcopenia have yet to be fully elucidated, several studies have implicated decreases in mitochondrial function and a corresponding increase in mitochondrially mediated cell death (apoptosis) as factors contributing to this age-induced decline (4,8).…”

“…The dramatic effects of aging on the physiological and biochemical aspects of muscle have an important role in regulating the progression of sarcopenia and in restricting the plasticity of aged muscle (22). Therefore, the purposes of this study were to assess the adaptive potential of young (5 mo) and aged (35 mo) muscle to 7 days of denervation and to ascertain whether regulators of autophagy are altered as a consequence of aging.…”