My primary research focus is on understanding the impact of age-related changes in skeletal muscle mass and contractile function in health and disease, the mechanisms contributing to these changes, and identification of therapeutic strategies for preserving muscle. Our initial research in this area established that impairments in skeletal muscle contribute to the reduced whole body exercise capacity seen with aging independent of a reduction in muscle oxygen delivery. Strikingly, we showed that long term reduction in energy intake (caloric restriction) could completely prevent the normal age-related decline in skeletal muscle function and provided the first indications that this likely occurred through maintained proteostatic mechanisms. In contrast, we showed that long term endurance training could not prevent the age-related decline in muscle mass and function, despite increasing mean lifespan and reducing age-related replacement fibrosis of the heart.
In evaluating the applicability of the mitochondrial theory of aging to aging of skeletal muscle, over the past several years we have been working towards identifying the nature, magnitude, and causes of mitochondrial dysfunction in striated muscle with aging, with the aim of understanding the therapeutic potential for targeting the mitochondrion. Our work has highlighted the importance of using analytical methods that preserve mitochondrial structure when addressing this question, and has revealed that persistent denervation, rather than mitochondrial dysfunction, is a primary cause of skeletal muscle atrophy and contractile dysfunction in advanced age. Interestingly, we also showed that some of the mitochondrial dysfunction seen in advanced age is secondary to the accumulation of persistently denervated muscle fibers in human skeletal muscle in advanced age. Further to this, we have established that the accelerating phase of muscle atrophy with aging is coincident with the accumulation of persistently denervated muscle fibers and a transcriptional and microRNA profile indicative of a failed reinnervation response.
In stark contrast to the declines seen with normal aging, in world class octogenarian athletes, who perform remarkable feats of athleticism at an age better known for impaired mobility and loss of independence, we have found that a primary explanation for their superior protection of muscle mass and function relates to an attenuated decline in the numbers of the smallest functional units of muscle, the motor units (=a motor neuron and the muscle fibers it innervates). Additional studies are showing that whereas mitochondrial function is not better preserved in these individuals, they exhibit several indices of superior reinnervation and neuroprotection relative to non-athlete but otherwise healthy octogenarians. As such, these results have highlighted the importance of preserving the motor unit rather than mitochondrial function in seeking strategies for attenuating the decline in skeletal muscle mass and function with aging.
Building upon this foundation knowledge in aging, we are now embarking on studies to understand mechanisms of skeletal muscle atrophy and contractile dysfunction in other settings such as tobacco smoking related disease (e.g., chronic lung disease), cancer cachexia, and amyotrophic lateral sclerosis.
- Amyotrophic Lateral Sclerosis
- Aryl hydrocarbon receptor
- Cancer Cachexia
- Motor neuron
- Motor unit
- Muscle atrophy
- Neuromuscular junction
- Neuronal excitotoxicity