Mechanisms of skeletal muscle aging: insights from Drosophila and mammalian models

Abstract

A characteristic feature of aged humans and other mammals is the debilitating, progressive loss of skeletal muscle function and mass that is known as sarcopenia. Age-related muscle dysfunction occurs to an even greater extent during the relatively short lifespan of the fruit fly Drosophila melanogaster. Studies in model organisms indicate that sarcopenia is driven by a combination of muscle tissue extrinsic and intrinsic factors, and that it fundamentally differs from the rapid atrophy of muscles observed following disuse and fasting. Extrinsic changes in innervation, stem cell function and endocrine regulation of muscle homeostasis contribute to muscle aging. In addition, organelle dysfunction and compromised protein homeostasis are among the primary intrinsic causes. Some of these age-related changes can in turn contribute to the induction of compensatory stress responses that have a protective role during muscle aging. In this Review, we outline how studies in Drosophila and mammalian model organisms can each provide distinct advantages to facilitate the understanding of this complex multifactorial condition and how they can be used to identify suitable therapies.

Fig. 1.

Morphological changes in skeletal muscles during aging in mammals. Muscle aging is characterized in mammals by a decline in the regenerative capacity, caused by a reduction in the number and function of muscle satellite cells (shown in blue). A decrease in the overall muscle strength and mass due to a decrease in the number and size of type IIb fibers (pink) and, to a lesser extent, type I fibers (red), is accompanied by defects in neuromuscular junctions and innervation (black). As the muscle ages, cycles of denervation and re-innervation eventually lead to changes in fiber-type composition, with a proportional increase in type I fibers (red), and grouping (stacking of red fibers). An accumulation of interstitial adipocytes (yellow) and decreased capillarization (not shown) are also observed. In Drosophila, defects in neuromuscular junctions have been described but there is currently no evidence for the presence of age-related changes in muscle mass that are seen in mammals.

Fig. 2.

Intracellular changes in muscle fibers during aging in mammals and Drosophila. (A) During aging, mammalian muscle fibers progressively accumulate damaged proteins in most cellular compartments, including the sarcomeres (red), which show loss of organization and structure (myofibril is shown in pink). Lysosomes (yellow) accumulate lipofuscin deposits and have decreased capability for degradation, resulting in improper turnover of organelles. Abnormalities affecting mitochondria (green) include decreased respiratory capacity, increased loss, abnormal size and irregular distribution. Misfolding and aggregation of membrane proteins of the sarcoplasmic reticulum (blue) can result in tubular aggregates and improper calcium handling in old age. Nuclei (gray) have DNA damage and epigenetic changes, loss of nuclear membrane integrity (due to damage of nuclear pore components), and can be lost during syncytial apoptosis (black star), which can result in changes in myofiber size without myofiber death. Similar intracellular changes, apart from changes in myofiber size, have also been described in Drosophila muscles during aging (not shown). (B) Staining of Drosophila indirect flight muscles from young (1 week old) and old (8 weeks old) flies with antibodies for Sod2 (mitochondria; green), poly-ubiquitin (protein aggregates; red), and phalloidin (F-actin, a component of sarcomeres; blue). Drosophila muscles display extensive protein damage and organelle dysfunction in old age. The number and function of lysosomes declines during aging and strikingly results in the accumulation of poly-ubiquitin protein aggregates. Although mitochondria (green) are homogeneously distributed along myofibrils (blue) in young age, they are enlarged (*) or absent from certain areas of the fiber in old age. The panel in the bottom left corner is a zoomed version of the section marked by the dashed line box directly above. (C) A transmission electron micrograph of Drosophila indirect flight muscles from old flies highlights the presence of mitochondria with ‘swirls’ of abnormally arranged inner cristae (arrow). These defects are normally not seen in young flies (not shown). Scale bar: 10 μm (B); 1 μm (C). See the main text for a more comprehensive description of the age-related cellular changes in mammalian and Drosophila skeletal muscles.