Muscle Involvement in Amyotrophic Lateral Sclerosis: Understanding the Pathogenesis and Advancing Therapeutics

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal condition characterized by the selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. Muscle involvement, muscle atrophy, and subsequent paralysis are among the main features of this disease, which is defined as a neuromuscular disorder. ALS is a persistently progressive disease, and as motor neurons continue to degenerate, individuals with ALS experience a gradual decline in their ability to perform daily activities. Ultimately, muscle function loss may result in paralysis, presenting significant challenges in mobility, communication, and self-care. While the majority of ALS research has traditionally focused on pathogenic pathways in the central nervous system, there has been a great interest in muscle research. These studies were carried out on patients and animal models in order to better understand the molecular mechanisms involved and to develop therapies aimed at improving muscle function. This review summarizes the features of ALS and discusses the role of muscle, as well as examines recent studies in the development of treatments.

Mitochondrial Dysfunction in Sporadic Amyotrophic Lateral Sclerosis Patients: Insights from High-Resolution Respirometry

“…Mutations in genes encoding complex I subunits have been found in ALS patients, and postmortem examinations have revealed reduced complex I activity in the motor neurons of ALS patients. In addition, animal models of ALS have shown that increasing complex I activity can improve motor function and prolong lifespan in these animals, suggesting that targeting complex I could be a potential treatment option for ALS [ 70 ]. Hor et al, in their study, demonstrated decreased mitochondrial respiration and increased glycolysis in ALS patients.…”

Edaravone: A Novel Possible Drug for Cancer Treatment?

“…Due to its lipophilic formulation, when administered intravenously, edaravone can easily penetrate the blood-brain barrier (BBB) and is minimally affected by P-gp efflux [109]. Additionally, edaravone exhibits keto-enol tautomerism, which significantly influences its action as a scavenger of radicals, thus endowing it with antioxidant properties [110,111]. More specifically, edaravone acts as a scavenger for peroxyl radicals and peroxynitrite, providing cytoprotection and neuroprotection against oxidative stress.…”

“…More specifically, edaravone acts as a scavenger for peroxyl radicals and peroxynitrite, providing cytoprotection and neuroprotection against oxidative stress. By neutralizing ROS, such as the hydroxyl radical, peroxyl radical, hydrogen peroxide, peroxynitrite, and other compounds that contribute to neuronal degeneration, edaravone safeguards neurons in the brain and spinal cord, thereby protecting against neurological damage and motor neuron death [110,111]. Interestingly, there is evidence that edaravone protects neurons from oxidative stress by altering mitochondrial activity, but the exact mechanism of action is still unknown [112].…”

“…Inhibition of HepG2, MSTO-211H, TMK-1, and MCF-7 tumor growth in a dose-dependent manner [105][106][107][108] Cytoprotective: reduces cardiotoxicity, renal failure, and neurotoxicity [111][112][113][114][115][116][117] Weak cytotoxic drug [106,107] Antioxidant [115] Blocking NFκB activation [109] Limiting ROS production [121] Has an anticancer effect in MCF-7 and HT-29 in combination with paclitaxel or doxorubicin [110] Radioprotective [124,125,127,128] Reduces the occurrence of thyroid dysfunctions [131]…”